Time for a Revision on Gene Editing for Cholesterol?

One of several highly anticipated clinical trials presented at the 2023 American Heart Association meeting was the heart-1 study (NCT05398029) from Verve Therapeutics. Some leading voices have hailed this a “game-changer” and the dawn of a new era. This was a small study of 10 individuals with heterozygous familial cholesterolemia (HeFH) – a genetic disorder affecting ~1 million Americans which causes elevated low-density lipoproteins (LDL or “bad cholesterol”). Patients with this condition often experience heart attacks, strokes and die prematurely. Fortunately, we have many treatment options available to mitigate (but not completely eliminate) the increased risks these patients experience including at least three types of oral medications (statin drugs are the mainstay) and several injectable options which can be added on. Three injectable drugs target a protein called PCSK9 which is involved in the processing of LDL. Individuals who lack PCSK9 have very low LDL and experience very low rates of cardiovascular disease. Two of these are monoclonal antibodies (evolocumab & alirocumab), which are dosed every 2-4 weeks by the patient using a self-injection system, somewhat akin to insulin. These two drugs have been tested in large randomized clinical trials showing a reduction in major adverse cardiac events. A third (inclisiran) is an RNA drug, given in a doctor’s office twice per year. A mega-trial of inclisiran aimed at evaluating if it lowers major adverse cardiac events is ongoing.

The Verve approach is to use gene editing to knock out the PCSK9 gene in the liver. This involves a version of a technology which won the 2020 Nobel Prize called CRISPR to edit genes inside of cells. Verve uses a second-generation form of this called base editing which they believe is safer than earlier CRISPR methods, because it changes a single nucleotide without causing complete breaks in DNA. To get this drug into cells, Verve uses lipid nanoparticles, somewhat akin to what was used in mRNA vaccines for COVID. These lipid nanoparticles (LNPs) help the drug get into the cells but they are also inflammatory. This trial and prior animal data showed that there are significant biochemical abnormalities from the liver induced by the drug. Further other drugs which use earlier generation LNPs have also caused systemic inflammation, sometimes requiring drugs to treat fever and/or inflammation to mitigate symptoms. LNPs are also an area of ongoing, rapid advancement. Verve themselves have more advanced LNPs as do many other groups which may allow more precise targeting and, hopefully, fewer inflammatory and other side effects.

Now back to the trial. The trial showed moderate reduction in LDL levels -- about 50-60%. Similar in scale to the other approved drugs targeting PCSK9. Those drugs have the advantage of large trial datasets (>20,000 individuals each) and also massive clinical experience showing they are safe and reasonably effective. The only advantage with the Verve approach is a “one and done” approach that theoretically a single dose treatment may protect for life (as opposed to monthly or semi-annually for the existing drugs). The drug did cause significant abnormalities in liver related blood tests potentially due to LNPs and inflammation, which normalized over time. Whether there is permanent liver damage is unknown, but with a single dose this may not be the biggest concern.

More critically, two of the ten patients had severe cardiac complications – the very thing the drug is hoped to prevent. The first case was of a death due to cardiac arrest 5 weeks after treatment. This is hard to know what to make of – but is concerning, especially in light of the second case.

The second case had a myocardial infarction one day after receiving the drug. The investigators report that the patient had not disclosed having chest pain leading up to treatment. Blaming the patient is certainly an interesting approach. Prominent reporters have agreed and written that this was a high-risk population and possibly expected complication. Of concern, given the nature of HeFH, shouldn’t the research team have checked carefully for symptoms of chest pain? Presumably the patient told the doctors about symptoms afterwards. Did they check blood tests like Troponin or perform an EKG before infusion that might have been abnormal in a patient with unstable coronary disease? For certain, patients sometimes forget to tell doctors important things or downplay symptoms. But the converse also happens. After the fact, we may amplify the significance of minor symptoms which may or may not have been related. Hard to know without a lot more details – even then very difficult. Often there are stored blood samples in clinical trials. If one is available, a troponin test could be run on a pre-drug treatment sample to help answer the question.

But why would this even happen? Is there a reason to believe a link between a drug infusion and heart complications? We have learned that inflammation is an important contributor to heart attacks and progression of coronary artery disease. Many in the field of cardiology have built entire careers around this concept. Curiously, few have discussed this important potential mechanism of harm.

I believe this is a major strategic error. When I was in medical school, it was early days for biologic drugs based on antibodies. Scientists were just developing methods to make these drugs in ways that would not cause the body to have undesirable inflammatory effects due to the antibodies being developed in mice or other lab animals. Eventually, they got good at humanizing antibodies. Really good. That said, the first targets for these drugs were in the auto-immune/inflammatory and cancer spaces. Areas where existing drugs were insufficient – having lots of side effects on not achieving good control of symptoms. Some of these drugs had massive improvements in patients’ quality of life very quickly but they also had risks and unknowns. Over time, these risk were mitigated by advances in technology and the unknowns addressed with experience.

Verve has chosen to go after a target for which there are numerous existing drugs with the main presumed advantage of dosing once per life instead of twice per year. Hardly a major win. Why not develop the gene editing and LNP technologies further for other diseases where existing treatments are lacking or insufficient. Allow the LNP and CRISPR technology to advance further before leaping to important but somewhat manageable diseases like HeFH? This would seem to be a prudent approach.

Most troubling though is the reaction of the media and cardiology community. They have systematically played down the issues and limitations. There is potential for major impact for sure, but the journey doesn’t have to start here: this target, this disease, this point in time. It can be the right idea, but the wrong time.

Personally, I believe it is time to put a hold on VERVE-101, the drug used in this trial, and wait for the technology to mature further and demonstrate large scale safety in clinical practice for other targets. This is the approach used for monoclonal antibodies and seems prudent here as well.

I’m told that at AHA, many smart physicians and scientists are quietly talking about these adverse events but few are saying anything publicly. Conversely, Wall Street seems to see the issues. Last I checked the stock price is collapsing – down about 40% in the first morning of trading. Clearly, these concerns are on at least some other folks radar. This strongly suggests that there is an opportunity to improve our ability to discuss positives and negatives of scientific studies in academia and that we maybe haven’t quite hit the balance as yet.

Addendum: I continued more thoughts in this line, focusing on general principles of when this type of approach might make sense in a second post here: Editing the Question on Gene Therapy from Can We to When Should We?