What to do with an astonishing finding?
Once in a long while, a paper appears in the NEJM where the methodology appears rock-solid, but the results are so far from expectations that one is left not knowing what to think. In this case it’s a Canadian/Australian study involving 1,228 subjects on hemodialysis who were randomized 1:1 to a fish oil supplement or placebo and followed for 3.5 years for serious cardiovascular events. The results are nothing less than astonishing, not because there appears to be a benefit from fish oil (there is a long history of the study of potential health advantages of fish oil supplementation), but because the effect was enormous: for instance, the treatment group rate of myocardial infarction was half and the rate of stroke was a third of the placebo group. So, one ends up in the paradoxical situation that because the effect is so strong, it is less likely to be the result of chance, yet because its magnitude is completely at odds with our biological priors, it makes it suspect. Ideally, we would get a confirmatory study, perhaps from the NIH or a European agency, but so far, I see nothing in the registries. Fish-Oil Supplementation and Cardiovascular Events in Patients Receiving Hemodialysis; Fish Oil for Patients Receiving Hemodialysis — Red Herring or Great Catch?
An oral PCSK9 inhibitor
Results from a Phase 2 RCT of Merck’s enlicitide, an oral PCSK9 inhibitor, were very strong, showing a 57% decrease in LDL in the treatment arm, about on par with prior generations of injectable PCSK9 inhibitors (monoclonal antibodies Praluent and Repatha, RNAi Leqvio), and obviously more convenient (though enlicitide needs to be taken on an empty stomach). Expectations are that this will be sufficient for a late 2026/early 2027 FDA approval (with a confirmatory trial for impact on hard CV endpoints), especially since Commissioner Makary has granted the asset a national priority voucher. What comes next will be fascinating: how will this be priced? The voucher was granted in part on a commitment to affordability, with a promised 70% discount on the list price for patients buying direct (a paradigm shift that is currently gaining steam with GLP-1s), but then, what will be the list price, and how does that fit with the price that health insurers will pay? In addition, what limitations will the payers continue to put on use, particularly since over the last few years, evidence has continued to emerge that driving LDL from low (e.g. where one could get with a statin) to very low provides meaningful benefit to the broader population? How will the manufacturers of injectables (Novartis, Regeneron, Amgen) respond, and not to forget that AZ has its own oral PCSK9 inhibitor (though it is a bit earlier in the process than Merck’s)? It’s going to be an interesting battle with multiple players fighting for a $10B+ pie. Hopefully, the patients will be the winners. A Placebo-Controlled Trial of the Oral PCSK9 Inhibitor Enlicitide
The grandfather (grandmother?) of tumor suppressors gets a drug
Along with Rb, TP53 is the canonical tumor suppressor gene that everyone learns about in Genetics 101. It plays a key role in initiating apoptosis when DNA is damaged beyond repair and is very frequently mutated (i.e. inactivated) in cancer. Yet, there are no drugs that target TP53 in-use to date, probably because it is a lot harder to restore function of a protein than to inhibit it (cf. CF). Things may change with rezatapopt (PMV Pharmaceuticals), a small molecule that reactivates TP53 with a specific mutation (Y220C). In a phase 1 study with 77 participants with advanced, heavily pretreated, solid tumors harboring the relevant TP53 mutation, the 63 subjects treated at a therapeutic dose had a 22% response rate, with the rate jumping to 35% in ovarian cancer. A phase 2 in ovarian cancer is on-going. What I find puzzling though is that these studies used rezatapopt as monotherapy. Given the mechanism of action, you’d expect that activity would be optimal with a regimen including a DNA-damaging drug, such as an alkylating agent. Phase 1 Study of Rezatapopt, a p53 Reactivator, in TP53 Y220C–Mutated Tumors
A novel modality for a new type of target
A number of inherited diseases are linked to nucleotide repeat expansion of the source gene; these are notoriously difficult to target with therapeutic agents. Myotonic Dystrophy Type 1 is an example in which the transcript product of DMPK is contaminated by extraneous RNA hairpins (generated by the nucleotide repeats) that interfere with other proteins and thereby cause symptoms, primarily in skeletal muscle. A natural therapeutic approach would be RNAi to degrade the corrupted DMPK transcript, but getting siRNA into muscle is not obvious. To achieve this, the folks at Avidity Biosciences (now part of Novartis) are attaching their siRNA to a mAb targeting TfR1 (transferrin receptor 1), a membrane protein highly expressed on striated muscle. This antibody-oligo-conjugate (AOC) is internalized, allowing the siRNA to do its job. In a study of 38 patients with myotonic dystrophy, they were able to show with muscle biopsies that the AOC confers 1) a dose-dependent concentration of intracellular siRNA, and 2) a reduction in DMPK mRNA. Adverse events were generally manageable, with one major exception: one patient had a brain infarct most likely related to the drug. A pivotal study with long term functional endpoints is on-going. Dyne is following a similar approach, but with an ASO to block translation instead of an siRNA to promote degradation. Beyond myotonic dystrophy, one can easily imagine much broader applications of the AOC approach. An Antibody–Oligonucleotide Conjugate for Myotonic Dystrophy Type 1
Gene therapy for hearing
The first gene therapy approved in the US (Luxturna) was for a form of retinitis pigmentosa and since then, a large number of gene therapy programs have targeted the eye. There have been far fewer efforts directed toward inherited deafness even though, like the eye, the inner ear is a self-contained site propitious for gene therapy administration. This is why it’s exciting to see in the Journal results from Regeneron’s program for homozygous otoferlin defects which are responsible for 1-3% of cases of profound deafness. In a series of 12 patients, they administered a replacement gene packaged in an AAV1 vector into 15 inner ears, and 11 of the patients had very substantial hearing improvement, with some reaching whisper sensitivity. This is a remarkable success which gene therapy needed, and that will uniquely help patients because even though cochlear implants are effective, their frequency resolution is low with limited perception of pitch and timber. In addition, I found two elements particularly intriguing. First, because the gene is too large to package in a single AAV1 particle, they split it in two and recombination of the whole gene occurs in situ. Second, most of the patients were very young children, but two were 16, and they both recovered hearing in the treated ear. This creates a significant opportunity for the economics of the program to treat a substantial backlog of patients with the condition rather than only newly diagnosed infants. DB-OTO Gene Therapy for Inherited Deafness
Medical credit cards!?
Described in a Journal Perspective, a world that I was unaware of: that of medical credit cards, which are essentially loan instruments specifically designed for health expenses. A good deal if you can pay up before the grace period of 6-18 months, a terrible one if you cannot, and one that forecloses other avenues such as charity care. Unsurprisingly, they are frequently offered as an option in the offices of specialties that run toward the “cash-oriented” end of the spectrum: dentistry, podiatry, fertility, chiropractic. Debt by Design — Navigating the Hazards of Medical Credit Cards
On what it is to be human
And to conclude on a kinder note, a letter to the editor documenting the genetic make-up of the 12,000-year-old remains of a mother-daughter (or potentially two sisters) couple, where the younger adolescent woman had very short stature and severe skeletal abnormalities tracked to a homozygous defect of NPR2. It surely impeded her movement and ability to contribute to the group, but she was evidently cared for as there was no sign of nutritional stress beyond what is found in this population, and she was buried in an embrace with her first-degree relative, mother or sister. A 12,000-Year-Old Case of NPR2-Related Acromesomelic Dysplasia
The New England Journal of Medicine is a premier weekly medical journal covering many topics of interest to the health sector. In this series we offer an opinionated perspective on selected highlights that might be of interest to our clients and others.