Leading a pharma company is forever a Dickensian bargain, the best of times, the worst of times.  Scientific breakthroughs bring highs, unexpected failures and regulatory scrutiny supply the lows.

Pharma had a moment in the sun during COVID, producing treatments and vaccines in record time.  The era of good feeling is long gone. Antivaxxer conspiracist Robert F Kennedy Jr. is, dishearteningly, getting airtime. More rational voices ask if everyone needs an annual COVID booster or only those at greatest risk? It’s a fair question but it’s a topic that transcends pharma CEOs’ ability to manage. Everything COVID is political dynamite. Absent a nasal spray that actually stops spread (and leaves out the microchips), anything about vaccines will be fodder for political combat.

Which makes the pharma industry’s behavior in a number of other areas so puzzling.

On the one hand Merck, BMS, and PhRMA (the pharma industry’s trade association) are going all-in to fight Medicare’s authority to bargain for lower drug prices. Chances are they will lose in court; certainly they will suffer in the court of public opinion.

On the other hand, pharma is AWOL on a few key issues where it could be building consumer trust and accelerating treatments against chronic disease. 

1. On generic drug shortages, pharma continues to look the other way instead of rolling up its sleeves to help solve supply chain issues;

2. There is a conspiracy of silence about new anti-Alzheimer’s drugs; most know they are very unlikely to slow the disease, yet few pharma leaders will say so. In time, all will bear the fallout of that silence.

3. Drug companies developing new anti-obesity medications (“AOMs”), which so far do appear to work well, are dropping the ball on post-trial and long-term outcome research. Did I meet the clinical trial metric? Yes? Check. No, actually; slowing or curing chronic disease will take a lot more work than checking the box.

Each of these acts of omission will play out over different time horizons. Looking ahead a couple of years, though, pharma will rue these missed opportunities. The political and economic climate will be more adversarial as more drugs go generic, as Alzheimer’s incidence and the failure of new drugs becomes clear, and as the demand for obesity drugs grows rapidly. Pharma will lose control of the narrative, having lost public trust, and will have only itself to blame for the inevitable regulations and investigations that result.

Going deeper on each of these topics …

Drug Shortages

The critical shortage of cancer drugs is getting worse. A few weeks ago, I outlined a way to address shortages, building on learnings from Operation Warp Speed.  Since then, the volume of concern expressed by oncologists has only gotten louder. (See e.g. Oncologists urge Congress to act, Cancer drug shortages should have patients rioting in the streets, & I can’t guarantee your next round of chemo).  

Amidst this outcry, from the White House and pharma we have heard … nothing.  Total silence.  Fixing generic drug supply chains is hard but not unsolvable. And it matters, yes, even to pharma companies after their drugs go off patent. Ninety percent of drugs prescribed are generic. Yet no resource-rich pharma company has stepped up, including any of those that used to make the drugs in shortage when they were branded.  Not my problem!  I’m waiting for the White House and Congress to get their act together.  Or perhaps, to be cynical, the pharmas look fondly on generic drugmakers’ failures since it bolsters their argument that drug buyers should continue to buy branded drugs even after patents expire to ensure supply and quality.

Maybe, but if so, it’s a huge miss in building trust.  Putting together a coalition of companies to solve drug shortages, to help build new ingredient sourcing and manufacturing in the US would be a welcome practical and PR win. It could even be a nice investment over time.  Every drug ultimately goes generic.  Why not own a stake in new domestic supply chain? Whether or not your company makes or sells the generic, you could still earn a piece of it.  So that’s the first pharma fail. 

Anti-Amyloid Hoopla

Number two is worse:  the new Alzheimer’s drugs.  Last week the FDA approved a new anti-amyloid drug, lecanemab (Leqembi), so-called because it seeks to slow Alzheimer’s progression by clearing out clumps of amyloid protein in the brain.  FDA’s approval of another anti-amyloid, aducanumab, last year, overriding the negative recommendation of an outside medical advisory panel, was so controversial that a majority of panel members resigned and Medicare, in effect, refused to cover it.  In the FDA’s view, lecanemab produced sufficiently good results in terms of slowing cognitive decline. The overall impact on the 28 point scale used to assess cognitive function was very small and benefits were not seen across the treatment group. The drugs carry significant risk of brain swelling or hemorrhage and will be administered (if neurologists have their way) sparingly until we understand how widespread these are.

Still, you might say, we’ve got nothing right now that works against Alzheimer’s? Why not this?   

If anti-amyloids were new to the treatment scene, sure, that makes sense. Only that’s not the case. Pharma company after pharma company has banged it’s head against the amyloid door, with over forty clinical trials to date.   The drugs do what they are designed to do. That is, they clear amyloid plaques.  The problem is, until the latest trial, there was zero evidence that they slowed clinical progression, and in some cases, made things worse. Every drug company that tried to develop an anti-amyloid drug has failed except Eisai (the company that developed lecanemab), and, potentially, Eli Lilly, which has a similar drug in trials. 

But wait, if the drug class has such a dismal track record, why is everyone celebrating?  Because for almost a quarter century, Alzheimer’s research has fixated on a belief that amyloid buildup (and perhaps that of another protein called tau) is either the cause or the primary driver of Alzheimer’s.  No one questions that amyloid buildup and tau tangles are characteristic signs of Alzheimer’s.  But presence is not causation. 

When offered, at the turn of the century, it was a provocative and plausible theory, and it made sense to understand if amyloid buildup drove Alzheimer’s.  Fast forward a quarter century and it has been pursued, literally, to death.  Today, the amyloid hypothesis remains the leading “explanation” for Alzheimer’s progression although we know it’s not true.

That’s a strong statement.  So don’t take my word for it.  Take the word of Eisai, the drug company that developed lecanemab.  Here’s what they say in their submission to FDA about what causes Alzheimer’s:

“Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder of unknown etiology and the most common form of dementia among older people … Current understanding is that AD begins with structural and biological changes in the brain many years before the emergence of clinical symptoms.” [emphasis added]

In other words, shrug, we don’t know. And in the world of Alzheimer’s research, this kind of vagueness is accepted boilerplate, itself a kind of outrage.  We don’t know what causes it, and whatever it is, it’s due to a number of factors.  Wait, I thought it was amyloid buildup. Because that’s what we’re targeting with these drugs, right? Stop amyloid buildup and the disease stops. Only it doesn’t. Twenty-five years into the war on cancer, we’d identified key genetic mutations that drove tumor development and there was a sense, controversial at the time, now vindicated, that the immune system could be reprogrammed to attack some tumors.  We are at roughly the same point, if we consider the amyloid hypothesis as the start line, with much less understanding of what it is we are actually fighting.

So why should we care? How does wider use of anti-amyloid drugs erode trust in the pharma industry writ large?  It matters because, as with the Leonard Cohen song, everybody knows.  Everybody knows amyloid isn’t “it” and clearing amyloid is very unlikely to get us closer to one of perhaps many contributing drivers. It has to be upstream of amyloid. Clearing it after its formed isn’t going to help us understand how it formed in the first place, and if the time and place of that formation actually tells us how the disease works. No one in a leadership position is willing to say that. They will say, we were not able to figure it out. What their scientists are saying behind closed doors is: the science isn’t there. We are shooting the messenger without understanding the message. Let Eisai and Lilly market their treatments, carefully one hopes given the serious side effects, but let’s look elsewhere. We need to be honest with patients that other hypotheses, other avenues of treatment are much more likely to bear fruit.

To date, few researchers have gained as much visibility or traction for alternate hypotheses as amyloid enjoys. But as a group of Alzheimer’s researchers pursuing alternate paths wrote recently, we desperately need these, along with institutional and industry support. Absent that we will be far, far behind when the limitations of anti-amyloid drugs becomes clear.    

Which brings me to a final area that Big Pharma is setting itself up to fail:  the quality of post-trial data gathering.

Now that lecanemab will be covered by Medicare, prescribing physicians will be required to upload patient-related data to a data registry.  Prescribers will provide information about side effects including potentially severe brain swelling or hemorrhage; results of brain scans and fluid tests; and outcomes of cognitive testing.  Great, that will help us continue to generate data similar to what was generated in the confirmatory clinical trial.

What it doesn’t do is help us track what else is going on with other potential biomarkers like inflammation or insulin metabolism, biomarkers that have little to do with amyloid, but might be critical clues about alternative sources of pathology. Maybe this data will exist elsewhere in the patient record. Maybe not. Either way, we will lose valuable data and critical time that will help us accelerate parallel efforts if we are wrong about amyloid.  

Anti-Obesity Medications

Commitment to gather long-term data is an issue with new anti-obesity medications as well.

Unlike the Alzheimer’s drugs, the new anti-obesity drugs appear to work well — incredibly well — in managing blood sugar and driving weight loss. But again, we need to check our biases and not fall in love with our ideas. Just as we need to understand a range of biological indicators in Alzheimer’s, beyond what’s immediately valuable in the clinical trial, we need to gather a broader set of data points from people taking AOM’s to understand variation in drug response and side effects, and why these occur.

The history of AOMs is a cautionary tale. Drugs introduced in the early 2000’s that worked in a different way than new AOMs were ultimately pulled from the market since they seemed to cause, among some patients, severe depression and suicidal ideation.  The rationale to pull them was pretty clear; the drugs didn’t have a significant enough impact on weight to justify the risk. Yet we never really nailed down how or why the drugs caused such a bad side effect. The re-emergence of severe depressive episodes as a side effect would be more problematic now. The new drugs, we know, deliver significant benefit to people with obesity or Type 2 diabetes. So we need a proactive approach, now, in conjunction with wider prescribing to understand potential side effects and longer-term metabolic changes.

One of the most remarkable omissions in Lilly’s Phase II trial of their new triple-action AOM, retatrutide, is that it does not appear the drug company is systematically tracking whether participants regain weight since the trial ended. This is a critical question: the extent to which people regain weight after stopping medication.    

Like Alzheimer’s, obesity is a complex chronic disease caused or driven by multiple factors, genomic, environmental, metabolic, immunological, and neurological.  Disentangling how well a drug works and when requires an upfront discipline to gather (and publish) a broad range of participant data and continue to gather key data over time after the study is completed.

This is what the public expects pharma companies and drug researchers to do.  Figure out which drugs or combinations work, for whom, when, and why. Don’t just develop a drug that can be sold as widely as possible at the maximum price.  

Pharma companies could get ahead of public, regulatory, and ultimately congressional disaffection over drug prices if they wanted.  Solving chronic disease is neither a sprint nor a marathon.  It’s more like a series of triathlons back to back.  Approaching issues with an open mind, we will solve a few at first, then more, then more, and then, hopefully, we will have large-scale breakthroughs.  

We can get through the race faster, much faster with everyone’s involvement, especially current patients and those at greater risk in the future.  The necessary prerequisite for that is trust. 

Will pharmas have the courage and confidence to earn it?  Time will tell but current signs are not promising.