Most mammals make their own vitamin C. Humans can't. Most mammals also have no lipoprotein(a) in their blood. Humans do, and for about one in five of us, the level is high enough to raise the risk of heart attack and stroke.

Linus Pauling thought those two facts were connected, and that a particle we now treat as a cholesterol problem began as an answer to a much older one: how the body holds itself together.

Lipoprotein(a), usually shortened to Lp(a), is a particle that carries cholesterol, similar to LDL, with an additional protein attached called apolipoprotein(a). How much of it you have is largely inherited. Elevated levels are associated with cardiovascular disease, and genetic research supports a causal contribution. It is more than a number that happens to appear alongside illness. [Clarke and colleagues, 2009](https://pubmed.ncbi.nlm.nih.gov/20032323/)

I think Pauling was onto something bigger than Lp(a). Heart disease is, upstream, a problem with the vessel wall: its collagen, its lining, and how well it holds up under pressure over a lifetime. Lp(a) is a patch for that wall, useful when walls failed young and harmful when it stays in place for decades.

## What scurvy tells us

Because we cannot make it ourselves, vitamin C has to come from food. It is necessary for normal collagen production, and collagen provides structural support throughout the body, including in blood vessels.

Scurvy is what happens when that requirement goes unmet for long enough. Gums swell and bleed. Bruises appear. Wounds heal poorly. Small blood vessels become fragile. The connection between nutrition and the physical integrity of tissue becomes difficult to miss. [NIH vitamin C fact sheet](https://ods.od.nih.gov/factsheets/VitaminC-HealthProfessional/)

Scurvy is not heart disease in fast forward. It makes vessels leak, not clog. What it proves is that the wall is not a finished structure. It is rebuilt continuously, and when a key ingredient runs out, it comes apart.

We spend a great deal of time measuring what circulates through our blood vessels and far less measuring the vessels themselves. The tissue carrying that blood has to be maintained, day after day, for an entire lifetime. That is where I think the story starts.

## The wall comes first

The standard story of heart disease starts with cholesterol in the blood. I think it should start with the wall. High blood pressure, smoking, and diabetes all damage the arterial wall. Cholesterol-containing particles accumulate there, and inflammation follows. [NHLBI on coronary disease](https://www.nhlbi.nih.gov/health/coronary-heart-disease/causes)

Take blood pressure. We usually think of stiff arteries as a consequence of high blood pressure. In the Framingham Heart Study, the stiffness came first: people with stiffer aortas were more likely to go on to develop high blood pressure. [Kaess and colleagues, 2012](https://pubmed.ncbi.nlm.nih.gov/22948697/)

What makes an artery stiff is largely what happens to its collagen and elastin, and sugar is a big part of it. Glucose reacts with long-lived proteins like collagen to form cross-linking compounds called advanced glycation end products, which make tissue rigid. This happens slowly with age and much faster with high blood sugar, which is why people with diabetes develop stiff arteries young. In diabetic rats, a drug that breaks these cross-links restored the flexibility of the arteries within weeks. [Wolffenbuttel and colleagues, 1998](https://www.pnas.org/doi/10.1073/pnas.95.8.4630) The same sugar products also bind receptors on the vessel lining and help drive atherosclerosis there. [Serum AGEs and coronary disease in diabetes](https://pmc.ncbi.nlm.nih.gov/articles/PMC3369965/)

Cholesterol matters, but it does its damage by getting stuck in the wall, and the wall's own molecules decide how much sticks. Experimental work points to the retention of lipoproteins beneath the artery's inner lining as an early step in atherosclerosis. [Skålén and colleagues, 2002](https://pubmed.ncbi.nlm.nih.gov/12066187/)

The wall also decides how it ends. Most fatal heart attacks begin when the fibrous cap over a plaque cracks, and that cap gets its strength from collagen, just as skin and tendons do. [Libby, 2013](https://pmc.ncbi.nlm.nih.gov/articles/PMC3726161)

So the chain I see runs like this. Sugar, age, and pressure stiffen and injure the wall. Cholesterol-carrying particles get trapped in it. Years later, a weakened collagen cap tears. The particles in the blood are part of the story, but the wall is where it starts and where it ends.

## The skin as a window

If the wall is upstream, the skin should tell us something. Skin and arteries rely on the same kind of structural collagen, and sugar damage builds up in both to comparable levels. [Skin glycation and cardiac surgery outcomes](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323943/)

It does. Glycation in the skin can be measured by shining light on it, and the reading predicts heart disease. A 2025 meta-analysis found it to be a strong predictor of cardiovascular disease and death in general, and especially in people with diabetes or kidney disease. [Skin autofluorescence meta-analysis](https://pubmed.ncbi.nlm.nih.gov/41396304/) In a Dutch cohort of people with type 2 diabetes, the skin reading predicted future cardiovascular disease more strongly than cholesterol or blood pressure did. [Lifelines type 2 diabetes study](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802158/)

Stretch marks are the question I most want answered. In inherited connective tissue disorders like Marfan syndrome, stretch marks and aortic tears go together. [Genetics of thoracic aortic aneurysm](https://www.ahajournals.org/doi/10.1161/circresaha.113.300675) The link shows up outside those syndromes too. Among adults with thoracic aortic aneurysms, those with stretch marks had dissections or needed preventive surgery at younger ages, and earlier work in children with aneurysms found that stretch marks tracked faster growth of the aorta. [Striae and thoracic aortic dissection](https://pubmed.ncbi.nlm.nih.gov/35052365/) As far as I can tell, no one has tested whether ordinary stretch marks predict ordinary heart attacks. Someone should.

## Pauling's idea

In 1990, Matthias Rath and Linus Pauling proposed that Lp(a) helped compensate for the loss of vitamin C synthesis in our evolutionary history. During periods of scarcity, a mechanism that reinforced damaged tissue would have helped an animal survive, even if it carried a cost later in life. [Rath and Pauling, 1990](https://pubmed.ncbi.nlm.nih.gov/2143582/)

The way I picture it is duct tape. When the material underneath weakens, a patch holds it together long enough to get through a hard stretch. Lp(a) is that patch.

I admire Pauling's willingness to approach a medical question through chemistry. His broader concept of _orthomolecular_ medicine concerned changing the concentrations of substances normally present in the body. The term appears in his 1968 paper on orthomolecular psychiatry. [Pauling, 1968](https://pubmed.ncbi.nlm.nih.gov/5641253/)

## The chemistry behind the duct tape

The protein attached to Lp(a) resembles plasminogen, a component of the system that breaks down blood clots. In laboratory experiments, Lp(a) interferes with plasminogen binding and activation on fibrin, the protein mesh of a clot, which slows clot breakdown. It grips fibrin through lysine-binding sites, the same sites Rath and Pauling proposed blocking with lysine. [Experiments on fibrin and plasminogen activation](https://pubmed.ncbi.nlm.nih.gov/8187237/)

Holding a clot in place is exactly what you want when a vessel is leaking and the tissue underneath needs time to rebuild. It is exactly what you do not want inside a narrowed coronary artery. Same mechanism, different setting. That, in short, is the story of Lp(a).

## What other animals tell us

If Lp(a) stood in for vitamin C, the animals that lost the ability to make vitamin C should be the ones that carry it. That was the core of Rath and Pauling's case. They noted that Lp(a) appears in higher primates and guinea pigs, both unable to make their own vitamin C, and only rarely in other animals. [Rath and Pauling, 1990](https://pubmed.ncbi.nlm.nih.gov/2143582/)

Genetic work since then has made that pattern harder to see. Apolipoprotein(a) turns out to be limited to a subset of primates and, unexpectedly, the hedgehog. Many bats cannot make vitamin C either, yet bats are not among the animals known to carry Lp(a). [Genomic comparison of apo(a) across species](https://escholarship.org/uc/item/1c11c2t1) [Vitamin C synthesis in bats](https://www.nature.com/articles/260626a0)

The guinea pig, the main example outside the primates, is also in doubt. Rath and Pauling reported detecting apolipoprotein(a) in guinea pig blood using antibodies, but a later review of Lp(a) biology lists the guinea pig among research animals that do not express it. [Rath and Pauling's guinea pig study](https://pubmed.ncbi.nlm.nih.gov/2147514/) [Review of Lp(a) biology](https://pmc.ncbi.nlm.nih.gov/articles/PMC3547132)

The hedgehog is the strangest part of the story. Its Lp(a)-like particle was not inherited from an ancestor we share. It came from a separate copy of the plasminogen gene, roughly 80 million years ago, built from repeats of a different section of that gene. Like ours, it binds fibrin. [Lawn and colleagues, 1997](https://pubmed.ncbi.nlm.nih.gov/9342350/)

The animals do not support the narrow version of Pauling's idea, in which Lp(a) exists specifically because we lost vitamin C. They do support the broader one. Evolution built a fibrin-binding particle twice, by separate routes, which tells me it was doing something useful. Vitamin C was one pressure on the wall. It was not the only one.

The test I would want run next is whether hedgehogs make their own vitamin C. If they do, the hedgehog evolved its patch without any vitamin C problem to solve, which is exactly what the broader version predicts.

## Why the patch survived

Here is what I think happened. For most of human history, vessel walls failed for many reasons: scurvy in lean seasons, injuries, and inherited connective tissue weaknesses like Marfan syndrome, in which the aorta can tear in early adulthood. A particle that held clots in place and patched leaks would have kept some of those people alive long enough to have children. Its cost, plaque in the arteries decades later, arrived mostly after the reproductive years, where natural selection barely sees it.

That is why a harmful particle is so common. It is also why people with little or no Lp(a) show no disease from lacking it. [Lp(a) in vascular disease, cancer and longevity](https://pubmed.ncbi.nlm.nih.gov/22196058/) With enough vitamin C and modern medicine, most of us no longer need the patch, and we still pay for it.

## Lowering a number

The pelacarsen result is where this stops being theoretical, so it is worth being clear about what the drug does.

Your liver builds apolipoprotein(a), the protein that turns an ordinary cholesterol particle into Lp(a). To make it, liver cells first copy the gene's instructions into a messenger molecule, a working copy the cell reads from. Pelacarsen is a short, synthetic strand of genetic material designed to stick to that working copy. Once it sticks, the cell destroys the copy, so less of the protein gets made and less Lp(a) reaches the blood. In kitchen terms, the gene is the cookbook, the messenger molecule is a photocopied recipe on the counter, and pelacarsen shreds the photocopy before anyone cooks. It is given as a shot under the skin, and in earlier trials it cut Lp(a) by up to 80%. [HCPLive on pelacarsen](https://www.hcplive.com/view/pelacarsen-misses-primary-endpoint-in-lp-a-horizon-phase-3-trial)

HORIZON was the test that matters: does lowering Lp(a) actually prevent heart attacks and strokes? It enrolled 8,323 people who already had cardiovascular disease, meaning a past heart attack, stroke, or blocked arteries in the legs, and Lp(a) of at least 70 mg/dL. Half got a monthly pelacarsen shot and half got a placebo shot, on top of their usual treatment, and neither they nor their doctors knew which. Then the researchers waited years and counted cardiovascular deaths, heart attacks, strokes, and urgent procedures to reopen coronary arteries. [Design of the Lp(a)HORIZON trial](https://pubmed.ncbi.nlm.nih.gov/40185318/)

On September 4, 2026, Novartis reported the answer. Pelacarsen lowered Lp(a) substantially, but the people taking it did not have significantly fewer of those events than the people on placebo. [Novartis trial announcement](https://www.novartis.com/news/media-releases/novartis-announces-lpahorizon-phase-iii-topline-results-pelacarsen-patients-elevated-lpa-and-established-cardiovascular-disease-cvd)

You can argue that the drug came too late or did not lower Lp(a) enough. I think the problem is more basic. If Lp(a) is a patch, lowering it treats the patch and leaves the wall alone. The people in HORIZON already had diseased arteries. Whatever made their walls fail, whether glycation, pressure, inherited connective tissue weakness, or all three, was still there after the drug did its job.

The strongest objection is genetic. People who inherit high Lp(a) have more heart disease, and because genes are dealt at conception, independent of diet and lifestyle, that is good evidence that Lp(a) itself does harm. [Clarke and colleagues, 2009](https://pubmed.ncbi.nlm.nih.gov/20032323/) I agree that it does. A particle that holds clots in place will make a failing artery more dangerous. But making a failing artery more dangerous is different from being the reason it fails. Read together, the genetics and HORIZON tell me that Lp(a) raises the stakes of wall damage, and that removing it late does not undo the damage.

The National Lipid Association still recommends measuring Lp(a) after HORIZON, and so do I. A high level tells you something real about your risk. [National Lipid Association statement](https://www.lipid.org/?p=16349) What HORIZON shows is that lowering the number is not the same as fixing what it warns you about. I cover the trial, the market reaction, and the other Lp(a) drugs in development in [a separate essay](/1790116600000-pelacarsen-phase-3-what-comes-next).

## Following the question upstream

I am skeptical of the financial incentives in medicine. A business can earn recurring revenue by managing a condition indefinitely. Preventing that condition may have enormous human value without offering the same return to the business. There are perverse and conflicting incentives here, and they shape which questions receive attention and funding. A drug that lowers a number in the blood is a product. A healthy vessel wall is not.

The same standard applies to vitamins, and the vitamin side of this story had money in it too. Rath and Pauling patented vitamin C combined with lysine and similar compounds as a treatment for cardiovascular disease. Rath later promoted his own vitamin formulas as a cure for AIDS in South Africa while calling antiretroviral drugs toxic, until a court effectively ordered him to halt his operations there in 2008. A 2015 mouse study supporting the hypothesis came out of his own research institute. None of that makes the hypothesis wrong, but it deserves the same scrutiny I would give a drug company. [Rath and Pauling's patent](https://patents.google.com/patent/US5278189) [The Lancet on the 2008 ruling](https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2808%2960972-1/fulltext) [Cha, Niedzwiecki, and Rath, 2015](https://pmc.ncbi.nlm.nih.gov/articles/PMC4447075/)

In the Physicians' Health Study II, 500 mg of vitamin C daily did not reduce major cardiovascular events over an average of eight years among 14,641 male physicians aged 50 or older. [Physicians' Health Study II](https://pmc.ncbi.nlm.nih.gov/articles/PMC2586922/) That fits the wall argument rather than undercutting it. Most well-fed adults are not short on vitamin C, so extra pills had little to fix. Vitamin C is one input to the wall. Sugar, pressure, and inherited connective tissue quality are others, and no vitamin covers those.

Pauling asked the right question: why would the body make something that hurts it? My answer is that for most of our history, the wall failed first, and Lp(a) held it together. We have spent decades going after the patch. The next step is to measure and protect the wall itself: its collagen, its lining, its stiffness, and the sugar slowly hardening it.

I would like to see those tested together: vitamin C status, skin glycation, arterial stiffness, stretch marks, inherited Lp(a), and actual cardiovascular outcomes. None of this is a reason to drop proven treatment. It is a reason to ask what that treatment is missing.

Thinking from first principles means being willing to follow an idea far enough to test it, including the parts we most want to be true.

Lp(a) looks like an ancient patch for failing blood vessels. Why I think heart disease starts in the vessel wall, and what that says about pelacarsen.

Why Do Humans Have Lipoprotein(a)? A Patch for the Vessel Wall


I have been following pelacarsen for a while. I met Howard Weintraub at NYU Langone in New York, and I also spoke with Sam from Novartis. This has been more than an abstract drug-development story to me.

It is unfortunate that it did not work out as hoped.

On September 4, 2026, Novartis announced that pelacarsen had missed the primary endpoint in its Phase III Lp(a)HORIZON trial. The drug lowered lipoprotein(a), but the study did not demonstrate a reduction in cardiovascular events in the overall population. The company said the full data would be presented at an upcoming medical congress. [Novartis announcement](https://www.novartis.com/news/media-releases/novartis-announces-lpahorizon-phase-iii-topline-results-pelacarsen-patients-elevated-lpa-and-established-cardiovascular-disease-cvd)

I wanted to understand what had actually failed, how the drug was supposed to work, and what this means for the other treatments being developed. The difference between lowering a blood measurement and preventing a heart attack is the entire point of this story.

_Research checked September 22, 2026. This essay discusses the topline announcement; detailed HORIZON results were not available in the sources reviewed._

## Why there was so much interest

Lipoprotein(a), or Lp(a), is a cholesterol-carrying particle with an extra protein called apolipoprotein(a) attached. Its concentration is largely inherited. Genetic studies have linked variants in the LPA gene to both higher Lp(a) and greater coronary disease risk, supporting a causal role rather than a coincidental association. [Clarke and colleagues, 2009](https://pubmed.ncbi.nlm.nih.gov/20032323/)

That made it an attractive target. If a specific inherited exposure contributes to disease, perhaps selectively reducing that exposure could prevent some of the disease. But genetic evidence about lifelong exposure cannot tell us exactly what happens when a treatment starts decades later. A randomized outcomes trial has to answer that question.

## How an antisense drug works

Pelacarsen acts on the instructions used to make apolipoprotein(a). The liver reads the LPA gene and produces messenger RNA, which carries the information needed to assemble the protein. Pelacarsen is a short synthetic strand designed to bind to that RNA. An enzyme called RNase H1 can then cut the RNA in the resulting pair, reducing the instructions available for protein production.

The drug also carries a GalNAc sugar-based attachment that helps liver cells take it up. Less apolipoprotein(a) production means less material available to form Lp(a). This is targeted interference with gene expression, not an edit to a person's DNA. [Pelacarsen pharmacology and liver-targeting study](https://pmc.ncbi.nlm.nih.gov/articles/PMC12478598/)

The earlier evidence was encouraging. In the published Phase II study of 286 people with cardiovascular disease and elevated Lp(a), reductions were dose dependent, reaching a mean of 80% in the highest-frequency treatment group, compared with 6% with placebo. That study established substantial biomarker lowering. It was not designed to establish fewer heart attacks or deaths. [Phase II paper](https://pubmed.ncbi.nlm.nih.gov/31893580/) · [Trial registration: NCT03070782](https://clinicaltrials.gov/study/NCT03070782)

HORIZON was the much larger test of whether that biochemical achievement translated into a benefit patients could feel in their lives.

## What HORIZON tested

The registered study enrolled 8,323 people with established cardiovascular disease and Lp(a) of at least 70 mg/dL. Participants were randomly assigned to monthly subcutaneous injections of 80 mg pelacarsen or matching placebo. Participants and investigators were blinded to the assignment.

The primary outcome was the time to a first qualifying cardiovascular event: cardiovascular death, nonfatal heart attack, nonfatal stroke, or urgent coronary revascularization requiring hospitalization. The registry specifies analyses in both the overall population and those with Lp(a) of at least 90 mg/dL. [HORIZON protocol and registry: NCT04023552](https://clinicaltrials.gov/study/NCT04023552)

This was a secondary-prevention trial: participants already had cardiovascular disease. It tested an additional treatment on top of standard care, including lipid-lowering and blood-pressure therapies. It did not test whether treating otherwise healthy young people for several decades would prevent their first event. [Trial announcement](https://www.novartis.com/news/media-releases/novartis-announces-lpahorizon-phase-iii-topline-results-pelacarsen-patients-elevated-lpa-and-established-cardiovascular-disease-cvd)

Those details matter when interpreting a failure. They define the question that was asked.

## What the announcement leaves open

The result is disappointing because the clinical benefit was the reason to develop the drug. A lower laboratory value cannot substitute for that benefit.

But a failed primary endpoint is not a measurement of exactly zero effect. To understand the result, we need the treatment effect estimate and its confidence interval: the best estimate of what happened and how much uncertainty surrounds it. We also need the event counts, follow-up, achieved Lp(a) levels, treatment discontinuations, and safety results.

Several explanations are possible. The benefit might be smaller than anticipated. Starting treatment after disease is established might limit what can be changed. The duration or degree of lowering might matter. Or the result might reveal a more fundamental limitation in treating Lp(a) as a therapeutic target. These are possibilities to investigate, not explanations the announcement has established.

I am especially interested in whether the individual components of the endpoint moved in the same direction. A composite combines events of different severity and frequency. I also want to see the prespecified higher-Lp(a) analysis, with the statistical rules used to interpret it. Searching through subgroups until something looks positive would not rescue the original result.

I explored the older vitamin C and vascular-repair hypothesis in [my companion essay](/1759873328993-why-do-humans-have-lipoprotein-a-a-patch-for-the-vessel-wall). HORIZON does not prove that hypothesis. It gives us a reason to examine our assumptions carefully without pretending that the missing explanation has already been found.

## The financial impact

There was a substantial business expectation attached to this trial. Reuters reported that analysts had modeled $3 billion to $6 billion in peak annual pelacarsen sales. On the morning of September 7, Novartis shares were down 3.3% following the announcement. [Reuters, via MarketScreener](https://ca.marketscreener.com/news/novartis-shares-down-as-failed-cholesterol-drug-study-increases-pipeline-pressure-ce785bdbdf89f027)

<figure>
  <img src="/images/pelacarsen-financial-impact.png" alt="Two financial charts: Novartis shares fell 3.3 percent in the September 7, 2026 morning snapshot reported by Reuters; analysts had forecast 3 to 6 billion US dollars in peak annual pelacarsen sales." width="1800" height="1584" loading="lazy">
  <figcaption>Source: Reuters, September 7, 2026. The stock move is an intraday snapshot. The sales range represents analysts' expectations before the result, not revenue already earned or a loss booked by Novartis.</figcaption>
</figure>

A forecast for peak annual sales is not the value of a drug. Investors also have to consider the probability of approval, how long sales take to develop, margins, royalties, competition, and the years of protection remaining. Nor can a company's whole stock-market decline be assigned to one product. Reuters was already discussing pressure from other parts of Novartis's pipeline in the same report.

For that reason, I would not present the larger selloff around this period as a clean estimate of the money lost because of pelacarsen. The initial reaction and the sales forecasts show the scale of expectations. They do not isolate the drug's valuation.

The scientific and financial uncertainty are connected. If investors become less confident that lowering Lp(a) will prevent events, that changes how they value competing programs too. Whether that pessimism is justified will depend on their results.

## The other approaches

The pipeline is broader than pelacarsen. Different drugs intervene at different steps, with different dosing schedules and study populations. They still face the same requirement: demonstrate better clinical outcomes.

| Drug        | Developer        | Approach                         | Major outcomes trial                                                            |
| ----------- | ---------------- | -------------------------------- | ------------------------------------------------------------------------------- |
| Pelacarsen  | Novartis / Ionis | Antisense RNA targeting          | [Lp(a)HORIZON — NCT04023552](https://clinicaltrials.gov/study/NCT04023552)      |
| Olpasiran   | Amgen            | Small interfering RNA            | [OCEAN(a)-Outcomes — NCT05581303](https://clinicaltrials.gov/study/NCT05581303) |
| Lepodisiran | Eli Lilly        | Small interfering RNA            | [ACCLAIM-Lp(a) — NCT06292013](https://clinicaltrials.gov/study/NCT06292013)     |
| Muvalaplin  | Eli Lilly        | Oral inhibitor of Lp(a) assembly | [MOVE-Lp(a) — NCT07157774](https://clinicaltrials.gov/study/NCT07157774)        |

**Olpasiran** reduces apolipoprotein(a) production through RNA interference, another way of silencing the message used to make the protein. Phase II data showed reductions exceeding 95% at week 36 with certain doses. Amgen's program includes both an outcomes trial in people with existing disease and a separate primary-prevention study, OCEAN(a)-PreEvent, in people at high risk of a first event. That distinction could help address the question of when treatment begins. [Phase II results](https://www.amgen.com/newsroom/press-releases/2023/08/amgen-presents-late-breaking-phase-2-olpasiran-data-at-esc-2023) · [Amgen's August 2026 development update](https://amgen.gcs-web.com/news-releases/news-release-details/amgen-reports-second-quarter-2026-financial-results)

**Lepodisiran** also uses small interfering RNA, with an emphasis on sustained lowering. In the Phase II ALPACA study, the pooled 400-mg groups had a placebo-adjusted, time-averaged reduction of 93.9 percentage points between days 60 and 180. That is a biomarker result over a specified interval, not a 93.9% reduction in heart attacks. The larger ACCLAIM trial is designed to examine cardiovascular events. [ALPACA paper](https://www.nejm.org/doi/full/10.1056/NEJMoa2415818)

**Muvalaplin** takes a different route. It is an oral small molecule intended to interfere with the assembly of the Lp(a) particle, rather than silencing RNA. Its Phase II KRAKEN study also illustrates why comparisons require care: at the 240-mg dose, the placebo-adjusted reduction was 85.8% using an assay measuring intact Lp(a), but 68.9% using an apo(a)-based assay. How the particle is measured changes the reported number. [KRAKEN randomized trial](https://jamanetwork.com/journals/jama/fullarticle/2826683)

There are additional programs, including the siRNA drug **zerlasiran**, which has published Phase II results. That expands the number of ways researchers can test the biology, but it does not yet supply cardiovascular-outcomes evidence. [ALPACAR-360 paper](https://pubmed.ncbi.nlm.nih.gov/39556769/) · [NCT05537571](https://clinicaltrials.gov/study/NCT05537571)

These studies are not head-to-head comparisons. Ranking the drugs by their largest advertised percentage reduction would ignore differences in dose, assay, population, and follow-up. HORIZON is a reminder that the eventual ranking should depend on outcomes and safety.

## What I am watching next

The immediate priority is the full HORIZON presentation and paper. As of September 22, I have not found a confirmed congress name or presentation date in the company's announcement or the other sources reviewed. I would rather leave that date open than turn an expected conference appearance into a fact.

For the other major trials, these are the current registry estimates:

| Study                                                             | Estimated primary completion | What that date means                                                                    |
| ----------------------------------------------------------------- | ---------------------------- | --------------------------------------------------------------------------------------- |
| [OCEAN(a)-Outcomes](https://clinicaltrials.gov/study/NCT05581303) | March 31, 2028               | Expected collection of the final primary-outcome data; not a promised announcement date |
| [ACCLAIM-Lp(a)](https://clinicaltrials.gov/study/NCT06292013)     | March 2029                   | Estimated primary completion                                                            |
| [MOVE-Lp(a)](https://clinicaltrials.gov/study/NCT07157774)        | March 2031                   | Estimated primary completion                                                            |

These are planning dates, checked against ClinicalTrials.gov on September 22, 2026. They can change. Analysis and publication may follow later, and a sponsor may announce a different readout schedule.

When the HORIZON data arrive, I want to return to the absolute event rates, confidence intervals, individual endpoints, higher-Lp(a) analysis, and safety findings. That should let us say more about what failed and what remains plausible.

I had hoped this would give people another effective way to reduce their risk. It is disappointing that the trial did not establish that benefit. I am still following the field, and I would like the next essay to be about what the full evidence teaches us, rather than what we can infer from a headline.


Following pelacarsen from its antisense mechanism to the HORIZON setback: what the trial tested, the financial reaction, and the next Lp(a) studies to watch.

Pelacarsen Phase 3: Results, Financial Impact, and the Lp(a) Pipeline

Pelacarsen: A Disappointing Result, and What Comes Next


<figure>
  <img src="./images/work.webp" alt="work">
</figure>

Career and work make up a significant part of our lives. Over a lifetime, the average person spends 13 years—roughly 90,000 hours—at work((The average person spends 90,000 hours working over their lifetime, approximately 13 years if working 40 hours/week from age 20-65. Source: Dreams.co.uk https://www.dreams.co.uk/sleep-matters-club/your-life-in-numbers-infographic)). To put this in perspective: we spend 26 years sleeping((26 years or 227,916 hours sleeping, plus another 7 years trying to fall asleep - about one-third of our entire lives. Source: Dreams.co.uk https://www.dreams.co.uk/sleep-matters-club/your-life-in-numbers-infographic)), 19 years in marriage (median duration)((The median duration of marriages in the U.S. has remained at 19 years since 2010. Source: BGSU https://www.bgsu.edu/ncfmr/resources/data/family-profiles/payne-median-duration-marriages-fp-20-16.html)), and only 4 years with friends and family((People spend approximately 4 years with friends and family over their lifetime. Source: Chris Bailey https://chrisbailey.com/our-life-span-is-only-17-5-years/)). When you subtract sleep and work from our lives, we're left with merely 17.5 years of truly discretionary time((After subtracting obligatory tasks like sleep and work, we're left with as few as 17.5 years of truly discretionary time in our entire lives. Source: Chris Bailey https://chrisbailey.com/our-life-span-is-only-17-5-years/)). Work isn't just a way to pay bills; it's one of the defining pillars of human existence.

<figure>
  <img src="./images/week-life.webp" alt="life-blocks">
  <figcaption>https://waitbutwhy.com/2014/05/life-weeks.html</figcaption>
</figure>

Yet the stark reality is that many people, if not a silent majority, are dissatisfied with their chosen vocation. Recent surveys reveal that only 30% of workers are satisfied with their pay((Only 30% of workers say they are extremely or very satisfied with how much they're paid, with 80% citing pay hasn't kept up with cost of living increases. Source: Pew Research Center 2024 https://www.pewresearch.org/social-trends/2024/12/10/job-satisfaction/)), just 26% feel satisfied with promotion opportunities ((About a quarter are highly satisfied with their opportunities for promotion at work, while 36% cite lack of growth opportunities as a source of job dissatisfaction. Source: Pew Research Center 2024 https://www.pewresearch.org/social-trends/2024/12/10/job-satisfaction/)), and a staggering 71% want to change bosses((For the seventh annual survey in a row, a shocking 71% of U.S. staffers said they want to change bosses, with leadership and recognition being major factors in job dissatisfaction. Source: Conference Board 2024 https://www.conference-board.org/press/job-satisfaction-2024)). When we spend such a significant portion of our finite lives working, this dissatisfaction becomes an existential crisis.

This is an excerpt from _The Prophet_ by Kahlil Gibran (1923), which is in the public domain. You can read the [complete book here](/prophet.pdf). I hope it helps you along your journey and provides some additional new perspectives.

Thank you to Gregg Braden for turning me onto Kahlil Gibran.

<hr />

> Work is Love Made Visible

<pre>
Then a ploughman said, Speak to us of Work.

     And he answered, saying:


You work that you may keep pace with the earth and the soul of the earth.
For to be idle is to become a stranger unto the seasons,
and to step out of life's procession,
that marches in majesty and proud submission towards the infinite.


When you work you are a flute
through whose heart the whispering of the hours turns to music.
Which of you would be a reed, dumb and silent,
when all else sings together in unison?


Always you have been told that work is a curse and labour a misfortune.
But I say to you that when you work
you fulfil a part of earth's furthest dream,
assigned to you when that dream was born,

And in keeping yourself with labour you are in truth loving life,
And to love life through labour is to be intimate with life's inmost secret.


But if you in your pain call birth an affliction
and the support of the flesh a curse written upon your brow,
then I answer that naught but the sweat of your brow
shall wash away that which is written.


You have been told also life is darkness,
and in your weariness you echo what was said by the weary.

And I say that life is indeed darkness save when there is urge,
     And all urge is blind save when there is knowledge,
     And all knowledge is vain save when there is work,
     And all work is empty save when there is love;


And when you work with love
you bind yourself to yourself, and to one another, and to God.


And what is it to work with love?

     It is to weave the cloth with threads drawn from your heart,
     even as if your beloved were to wear that cloth.

     It is to build a house with affection,
     even as if your beloved were to dwell in that house.

     It is to sow seeds with tenderness and reap the harvest with joy,
     even as if your beloved were to eat the fruit.

     It is to charge all things you fashion with a breath of your own spirit,
     And to know that all the blessed dead are standing about you and watching.



Work is love made visible.



And if you cannot work with love but only with distaste,
it is better that you should leave your work
and sit at the gate of the temple
and take alms of those who work with joy.

For if you bake bread with indifference,
     you bake a bitter bread that feeds but half man's hunger.
And if you grudge the crushing of the grapes,
     your grudge distils a poison in the wine.
And if you sing though as angels, and love not the singing,
     you muffle man's ears to the voices of the day and the voices of the night.


~Kahlil Gibran, 1923
</pre>


Work is Love Made Visible


<figure>
  <img src="./images/soulless.webp" alt="Soulless Technology" style="display: none;">
</figure>

> I can't get no satisfaction
> — The Rolling Stones, 1965

We're uniquely obsessed with progress. No other species seems so relentlessly dissatisfied. Horses and carriages? Old. Cassette tapes? Bulky. Landlines? Not mobile enough. We've been this way since we first chipped flint into blades, tamed fire despite its danger, painted stories on cave walls while survival itself hung in the balance.

https://www.youtube.com/embed/nrIPxlFzDi0

Are we alone in this compulsion? Unlikely. Across the cosmos, across deep time, surely others have walked this path. The universe is too vast, too old, for us to be unique.

Yet look at what our progress has wrought. We have the richest economy in human history((Global GDP reached $100 trillion in 2022, yet wealth inequality has reached unprecedented levels - the 10 richest countries have per-capita purchasing power of $118,000 while the 10 poorest have just $1,600. Source: IMF https://gfmag.com/data/richest-countries-in-the-world/)), but record depression((5.7% of adults globally suffer from depression, with over 1 billion people living with mental health disorders - a 25% increase since COVID-19. Source: WHO https://www.who.int/news-room/fact-sheets/detail/depression)) and homelessness((In the U.S. alone, 771,480 people experienced homelessness in January 2024 - the highest number since data collection began, an 18% increase from 2023. Source: HUD https://www.huduser.gov/portal/sites/default/files/pdf/2024-AHAR-Part-1.pdf)). Modern medicine saves millions from ancient killers, while obesity((40.3% of U.S. adults have obesity in 2024; obesity causes 3.7 million deaths annually from chronic diseases worldwide. Sources: CDC https://www.cdc.gov/nchs/products/databriefs/db508.htm and WHO https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight)), inflammation, and heart disease run rampant. The internet connects eight billion humans, yet loneliness reaches epidemic proportions((24% of people globally experience regular loneliness; 30% of U.S. adults feel lonely at least weekly, with young adults hit hardest at 79%. Sources: WHO https://www.who.int/teams/social-determinants-of-health/demographic-change-and-healthy-ageing/social-isolation-and-loneliness and APA https://www.psychiatry.org/news-room/news-releases/new-apa-poll-one-in-three-americans-feels-lonely-e)). Real community feels like a relic.

These aren't just unfortunate side effects or growing pains. They reveal a pattern: when we build without asking why, when we innovate just to innovate or profit just to profit, our tools amplify problems rather than solve them. We've mastered how to build but forgotten to ask what's worth building.

This forgetting points to something fundamental we've lost: consciousness. From the Latin "conscientia," meaning "knowing with," consciousness implies self-awareness, wisdom, connection. Our ability to produce technology has far outpaced this deeper knowing.

Consider our relationship with Earth. We have one planet, perfectly positioned in the cosmos, neither too hot nor too cold for life to flourish. A gossamer-thin ozone layer protects us from radiation while trapping just enough heat. We're blessed with oxygen, water, and rainforests that form a living system of staggering complexity and fragility.

If honey bees vanished tomorrow, three-quarters of our food crops would lose their pollinators((75% of major food crops depend on pollinators. Of the 100 crops that provide 90% of the world's food, 71 are pollinated by bees. Colony losses reached 62% in 2024-2025, the worst ever recorded. Sources: UN FAO https://www.fao.org/newsroom/detail/Declining-bee-populations-pose-threat-to-global-food-security-and-nutrition/en and Penn State https://www.psu.edu/impact/story/protecting-pollinators/)). No more apples, almonds, or avocados. No coffee or chocolate. We'd survive on wheat and rice, but the diverse, nutritious foods that make life worth living would vanish. Everything hangs by such delicate threads.

Yet we poison the air, contaminate the water, bury our waste, and excavate caverns for nuclear refuse((Air pollution causes 8.1 million deaths annually, the second leading risk factor for death globally. 2.2 billion people lack access to safe drinking water, with 44% of wastewater returning untreated to the environment. Nuclear waste sites like Hanford contain 56 million gallons of radioactive material, costing over $100 billion to clean. Sources: State of Global Air 2024 https://www.stateofglobalair.org/resources/report/state-global-air-report-2024 and UNICEF https://www.unicef.org/press-releases/air-pollution-accounted-81-million-deaths-globally-2021-becoming-second-leading-risk)). We treat our only home like it's disposable.

Profit today, let tomorrow's children clean up the mess. But if each generation thinks this way, eventually there's no tomorrow left. We approach our own Rubicon, a point of no return where the damage becomes irreversible. Not just for us, but for every species that shares this planet.

The paradoxes are starkest in our digital lives. Social media promised connection; it delivered isolation. We have thousands of "friends" but no one to call in crisis. We doom scroll for hours, losing three days each month to our screens((31% of American adults doom scroll regularly, with rates reaching 51% among Gen Z. The average person spends 6 hours daily consuming media and believes they lose 3 days monthly to scrolling. Source: 2024 Talker Research https://www.livenowfox.com/news/talker-research-media-consumption-report-2024)). Meta's latest offering, Vibes, floods feeds with AI-generated video slop designed purely to hook attention and serve ads((Meta launched Vibes on September 25, 2025, a feed of entirely AI-generated videos. Users responded to Zuckerberg's announcement with "gang nobody wants this" and "Bro's posting ai slop on his own app." Source: Meta https://about.fb.com/news/2025/09/introducing-vibes-ai-videos/)).

<blockquote class="twitter-tweet"><p lang="en" dir="ltr">gang nobody wants this</p>&mdash; s (@sdw) <a href="https://twitter.com/sdw/status/1971325606005702798">September 25, 2025</a></blockquote>

<figure>
  <div style="margin: 20px 0;">
    <img src="/images/slop1.webp" alt="AI generated content example" style="width: 100%; height: auto; margin-bottom: 10px;" />
    <img src="/images/slop3.webp" alt="AI generated content example" style="width: 100%; height: auto; margin-bottom: 10px;" />
    <img src="/images/slop4.webp" alt="AI generated content example" style="width: 100%; height: auto; margin-bottom: 10px;" />
    <img src="/images/slop5.webp" alt="AI generated content example" style="width: 100%; height: auto; margin-bottom: 10px;" />
    <img src="/images/slop6.webp" alt="AI generated content example" style="width: 100%; height: auto; margin-bottom: 10px;" />
    <img src="/images/slop7.webp" alt="AI generated content example" style="width: 100%; height: auto;" />
  </div>
  <figcaption>Public backlash against tech billionaires pushing AI slop - selling digital cigarettes to the masses</figcaption>
</figure>

<script async src="https://platform.twitter.com/widgets.js" charset="utf-8"></script>

All this engineered addiction serves one purpose: consumption.

https://www.youtube.com/embed/PgU71nWCNeY

> "We buy things we don't need with money we don't have to impress people we don't like."
> — Fight Club

Echo chambers amplify division. Outrage travels faster than understanding.

We carry all human knowledge in our pockets, yet drown in misinformation. Conspiracy theories spread six times faster than truth. Deepfakes blur reality. Algorithms amplify extremism over wisdom. The information age has become the confusion age.

Artificial intelligence is the ultimate expression of this disconnect. We rush to automate everything, supposedly to create abundance, but really just to cut costs and maximize profits. Yet what's the endgame? When everyone uses AI, competitive advantage evaporates. Margins collapse to the cost of electricity and API fees. We're racing to the bottom, automating ourselves into irrelevance.

Helena Blavatsky warned in the 19th century of "soulless" beings, entities that mimic intelligence without consciousness. Now we hand healthcare, justice, and creativity to machines that don't know what any of it means.

And for what? This relentless efficiency doesn't create the abundance we're promised. Instead we get social credit scores that turn citizens into prisoners. Autonomous drones that make killing as easy as clicking a mouse. Deepfakes that obliterate any notion of truth. AI slop flooding every feed, every platform, optimizing for engagement while draining all meaning from human expression. Black Mirror looks quaint compared to what's already here. The dystopia isn't coming. We're building it, one algorithm at a time.

The economic paradoxes are equally stark. California's economy alone would rank 5th globally, yet tent cities sprawl beneath Silicon Valley offices where twenty-somethings make $300k. New York generates more wealth than entire nations while families sleep in subway stations. We can 3D print houses in days but "can't afford" to shelter humans. Apps deliver sushi in 15 minutes to those who pay $3000/month for studios, while food banks run empty miles away.

<figure>
  <img src="/images/homeless.webp" alt="Homeless encampment" style="width: 100%; height: auto;" />
  <figcaption>Tent cities in the shadow of billion-dollar tech campuses - the paradox of modern prosperity</figcaption>
</figure>

This isn't just market failure. It's what happens when central banks print trillions, inflating assets for those who own them while wages stagnate for everyone else. As Richard Werner documented in [Princes of the Yen](https://www.amazon.com/Princes-Yen-Central-Bankers-Transformations/dp/0765610493), credit creation concentrates wealth by design, not accident. Technology amplifies these distortions. AI won't fix what consciousness hasn't addressed: we have all the tools to solve homelessness, hunger, and basic human needs. We choose not to. We'd rather optimize ad clicks than optimize human flourishing.

<figure>
  <img src="/images/median-house-cost-and-income.webp" alt="Median house cost vs income chart" style="width: 100%; height: auto;" />
  <figcaption>The American Dream priced out - housing costs soar while incomes stagnate</figcaption>
</figure>

Technology doesn't solve inequality; it amplifies it. Like money revealing character rather than changing it, technology magnifies what's already there. How we build anything reveals how we build everything. Those with capital use AI to generate more wealth. Those without fall further behind. Educational technology widens the gap between connected and disconnected students. The gig economy delivers precarity disguised as flexibility. The pattern is consistent: our tools mirror our values, and our values prioritize extraction over care.

So where does it all go?

Technology and consciousness are parallel tracks of human evolution. The relationship between them determines our fate. When innovation exceeds wisdom, we get dystopia. Nuclear energy becomes nuclear weapons. Surveillance becomes oppression. Algorithms become manipulation.

When technology leads and consciousness lags, we get Orwell's 1984 as reality. China's social credit system scores humanity rather than serves it. Facial recognition turns public spaces into open-air prisons. Predictive policing criminalizes poverty. Digital currencies could become tools for total economic control. The technocratic dream of efficiency becomes a nightmare of dehumanization.

https://www.youtube.com/embed/a9sn4_Dpa00

This is the path of "might makes right," where those who control the technology control everyone else. Tech billionaires speak of humanity as a problem to be solved rather than a miracle to be cherished. Universal basic income proposals sound benevolent but could become digital breadlines, keeping the masses barely sustained while a technological elite accumulates unimaginable power.

AI systems already make decisions about human lives: who gets hired, who gets loans, who gets released from prison. These systems have no genuine understanding of what it means to be human.

When technology becomes the answer to everything, it devolves into pure materialism. Soulless, mechanical, dead. Everything optimized but nothing has meaning. Infinite entertainment but no joy. Constantly connected but never truly together. We can simulate any experience but lose touch with reality itself.

But there's another path, one we keep avoiding because it requires something harder than building machines: growing up.

The answer doesn't lie in AGI or ASI or whatever acronym comes next. We keep hoping the next technological leap will magically solve problems that aren't technological at their core. Loneliness isn't a software bug. Inequality isn't a hardware limitation. Environmental collapse isn't an optimization problem.

What we need isn't more processing power but more compassion. Not faster algorithms but deeper wisdom. Not virtual connections but real community. We need to remember what every indigenous culture knew: harming the Earth harms ourselves. We are not separate from nature, we are nature. The bees dying are us dying. The oceans acidifying are our blood turning poison.

This isn't mysticism. It's the most practical truth there is. Every living system is interconnected. Damage one part, damage the whole. Yet we treat Earth like a platform to be exploited rather than a living system we're part of. We treat each other as competitors rather than collaborators in survival.

The real evolution we need isn't technological but spiritual. Not in some religious sense, but in recognizing our fundamental interconnection. When you truly understand that your wellbeing depends on everyone else's wellbeing, you stop hoarding and start sharing. When you grasp that Earth's health is your health, you stop poisoning and start healing.

This shift in consciousness could transform technology from a weapon into a gift. Imagine AI serving genuine human needs rather than manufactured desires. Automation creating leisure rather than unemployment. Networks building understanding rather than division. We have all the tools needed to create something approaching heaven on Earth. What we lack is the maturity to use them.

<figure>
<img src="/images/flower.webp" alt="Flower of life" style="width: 100%; height: auto;" />
</figure>

But maturity can't be downloaded or coded. It must be earned through facing hard truths: that our current path leads to extinction. That infinite growth on a finite planet is suicide. That no amount of technology will save us if we don't save ourselves first.

The choice is stark. Continue our adolescent fantasy that more technology equals more happiness, and watch everything collapse. Or grow up. Develop the consciousness to match our capabilities. Learn to love the world and each other before it's too late.

Time is running out. Climate tipping points approach. AI systems grow beyond our control. Social fabric tears. The question isn't whether technology will advance. It will. The question is whether we'll advance with it, or let it drag us into a soulless future where everything is optimized except what matters: love, meaning, connection, life itself.

The ultimate purpose of technology will be whatever we choose, or whatever we allow to be chosen for us. But first, we need to become conscious enough to choose wisely.

The alternative is extinction. A final lesson for a species that could build anything except wisdom.

<figure>
<img src="/images/mars.webp" alt="Mars" style="width: 100%; height: auto;" />
</figure>


Recent writing

Why Do Humans Have Lipoprotein(a)? A Patch for the Vessel Wall

Pelacarsen: A Disappointing Result, and What Comes Next

Work is Love Made Visible

Soulless Technology

How to Build a Solar Backup System for Under $5,000

Gavin Mai

Recent writing

Why Do Humans Have Lipoprotein(a)? A Patch for the Vessel Wall

Pelacarsen: A Disappointing Result, and What Comes Next

Work is Love Made Visible

Soulless Technology

How to Build a Solar Backup System for Under $5,000