Tirzepatide in pole position
As previously described in this blog, GLP-1 agonists initially designed to treat glycemia in Type-2 diabetes are emerging as powerful weight loss agents in obesity independent of diabetic status. Recently, tirzepatide (Mounjaro, Lilly, approved May 2022) which combines GLP-1 and GIP activity has shown potential to be best in class, and this is supported by a 72-week study that randomized 2539 obese individuals to 3 different tirzepatide doses or placebo. The results are nothing short of spectacular with ~-21% mean change in weight at the optimal dose (10 mg/week subcutaneous) and better than semaglutide (Novo’s entry which is a pure GLP-1 agonist) with ~-16% change in weight and a higher incidence of nausea. Tirzepatide seems well positioned in winning the battle to address the enormous burden of obesity, but two comments: (1) while tirzepatide is only available for subcutaneous delivery, semaglutide also has an oral option which may increase acceptability; (2) in a non-diabetic obese population, neither tirzepatide nor semaglutide have yet been shown to improve hard morbidity end-points (e.g. MI, death) – but for semaglutide, there is an on-going trial with 17,500 patients looking to show that. No such study has been initiated to date for tirzepatide. If the semaglutide study is positive, Novo’s reps will be able to make claims that Lilly’s reps won’t match. Tirzepatide Once Weekly for the Treatment of Obesity
A second revolution in breast cancer?
Until the mid-90s, a diagnosis of Her2+ breast cancer was catastrophic news. Then came trastuzumab (Herceptin) targeting Her2, a quasi-miracle drug that extended survival to years where patients previously had months, and at the same time ushered the biotech revolution in cancer. Twenty-five years later, we may see the same thing with an extraordinarily potent antibody-drug conjugate combining trastuzumab and deruxtecan (Enhertu, Daiichi/Astra Zeneca). A few weeks ago, a paper came out with one the strongest survival responses I have ever seen in advanced cancer for Her2+ patients who had exhausted their response to Herceptin. Now we get results in a class of patients with low expression of Her2 (who represent about 60% of so-called “Her2 negative” patients) for whom straight Herceptin was shown to not work a long time ago. Again, there was significant survival advantage (23.4 vs. 16.8 month) for the 373 patients on trastuzumab deruxtecan vs. the 184 patients on standard of care regimen. Two comments: first, these were advanced heavily pretreated patients and so we may see even greater benefits earlier in the disease; and second, Her2 status assessment is notoriously fickle because it relies on an immunohistochemistry tissue preparation reviewed by a pathologist – it may be that we have not reached the Her2 threshold limit of applicability of Enhertu. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer; DESTINY-Changing Results for Advanced Breast Cancer
A leap forward in xenotransplantation
A fascinatingly detailed report of the recent transplantation of a pig’s heart to a 57-year-old man previously widely publicized in the general media. A few nuggets of particular interest:
- The pre- and post-transplantation clinical course of the recipient was extremely rocky: mechanical cardiac support, ECMO, renal replacement therapy, parenteral feeding, periods of intubation, peritonitis… likely for reasons that had limited relation to the xenotransplant;
- The onset of graft failure at day ~48 remains mysterious; the rapid progression (within a week) is counterintuitive with the 6-week delay of onset. The leading hypothesis seems to be porcine CMV (cytomegalovirus infection) immunologically interacting with HHV-6 (human herpes virus 6) in the patient, but there is no certainty;
- The heart was obtained from a 10-gene-edit 110 kg pig (Revivicor) with 4 knock-outs (GGTA1, B4GALNT2, CMAH to prevent immunogenic glycosylation, GHR to avoid further growth) and 6 human regulatory knock-ins (CD46 and CD55 for the complement system, THBD and PROCR for coagulation, and CD47 and MOX1 for inflammation).
Given the scope for further genetic tuning of the donor animals, it seems that likely that xenotransplants will eventually work. In the meantime, spare a thought of thanks to the poor soul who went through this ordeal for making a very sizable contribution to this technology with the potential to help a great many. Genetically Modified Porcine-to-Human Cardiac Xenotransplantation
GWAS, Regeneron and Geisinger, and liver disease (Part 2)
Four years ago Regeneron and Geisinger reported the discovery of a protective variant (in gene HSD17B13) for liver disease using genome wide association studies of 100,000 patients. Trials with siRNAs against this target are on-going. Now Regeneron and Geisinger are repeating the analysis with an additional 400,000 samples from the UK Biobank, and they identified that loss of function of CIDEB (a gene encoding a protein involved in processing of hepatic lipid droplet) is also protective for liver disease. The effect seems stronger than that seen for HSD17B13, but since mutated CIDEB is less prevalent, it took a bigger sample size to see it. Soon to be seen: siRNAs against CIDEB? And so I ask the question that I posed four years ago again (though the rankings have changed): there are about 30 biopharma companies larger than Regeneron, and about 90 US health systems larger than Geisinger – are they leveraging these types of opportunities?
MM PFS ≠ MM OS
Treatment of patients with multiple myeloma (MM) often involves an autologous cell transplant, but there have been questions whether this has an impact on survival. In a long-term study (~7 years of follow-up) of about 722 MM patients randomized to transplant + chemotherapy vs. chemotherapy alone, investigators tracked progression free survival (PFS) and overall survival (OS). The PFS Kaplan-Meier curves show a large separation between the two groups with a highly significant delay in progression for those receiving a transplant. Remarkably, the OS Kaplan-Meier curves are virtually superimposed, there is no survival advantage. The figure has to be seen to be believed. There might have been a quality of life benefit in the transplant group with delayed progress, but that has to be weighed against the fact that a bone marrow transplant is no picnic. Triplet Therapy, Transplantation, and Maintenance until Progression in Myeloma
The New England Journal of Medicine is a premier weekly medical journal covering many topics of interest to the health sector. In this monthly series we offer an opinionated perspective on selected highlights that might be of interest to our clients and others.