The new Humira?
It’s not that often that you see industry-sponsored head-to-head studies of one biologic vs. another, but Abbvie took the plunge comparing risankizumab (Skyrizi) to ustekinumab (Stelara, J&J) a leading therapeutic for Crohn’s disease, a notoriously hard indication because of its unpredictable manifestations. The risk paid off for Abbvie: a significant advantage was seen for risankizumab which provided clinical remission in 60.8% of patients. Abbvie probably had no choice: ustekinumab biosimilars are expected on the market by 2025; absent a clinical advantage, most payers would have demanded patients use ustekinumab. As a result of this success, the street now sees $20B in revenue from Skyrizi in the horizon 2030. Risankizumab versus Ustekinumab for Moderate-to-Severe Crohn’s Disease
More GLP-1 triumphs
A couple more indications where the impact of GLP-1 agonists is increasingly obvious. One is diabetes-related chronic kidney disease (CKD) in which semaglutide markedly slowed the decline of kidney function over the span of a year in a placebo-controlled study (the study was actually stopped early by the independent monitoring committee for efficacy). A fascinating question is whether this benefit was due to an antidiabetic effect or an independent renal-protective effect – we don’t know for sure but studies in CKD patients without diabetes are on-going so we should find out.
The other condition is MASH (ex-NASH) where semaglutide has shown efficacy in reducing inflammation but not fibrosis in the past. This time dual agonists tirzepatide (Lilly’s Mounjaro, GLP-1+GIP agonists) and survodutide (Boehringer, GLP-1+glucagon receptor agonists) both showed reduced inflammation and decreased fibrosis in RCTs. It would be very surprising if, in the long-run, this does not also decrease progression to cirrhosis, the ultimate source of morbidity in MASH, but it is not proven (and will be hard to show without multiyear studies).
It’s important to note that both CKD and MASH are conditions where it’s notoriously difficult to see therapeutic effects, as biomarkers are intrinsically noisy. The fact that we are seeing clear evidence of beneficial activity is a testament of the potency of the GLP-1 mechanism. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes; Tirzepatide for Metabolic Dysfunction–Associated Steatohepatitis with Liver Fibrosis; A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis
In the footsteps of inclisiran with plozasiran and zodasiran
The discovery via population genetics that loss-of-function mutations of PCSK9 are cardioprotective eventually led to the development an interfering RNA specifically targeting PCK9 (inclisiran/Leqvio, Novartis/Alnylam). In a classic rinse and repeat strategy, Arrowhead Pharmaceuticals went after two other targets identified by essentially the same process: APOC3 and ANGPLT3, again targeted with RNAis (plozasiran and zodasiran, respectively), and the company has achieved the rare distinction of having two articles on two different drugs in the same issue. Both were reporting on phase 2 placebo-controlled studies on patients with mixed hyperlipidemia and both reported a highly significant decrease in triglyceride levels. Effect on other metabolic parameters were similar in some areas yet different in others – the one that stood out to me being that plozasiran increased HDL by ~50% while zodasiran decreased it by ~20%. Arrowhead has now decided to focus on plozasiran which is now enrolling a large Phase 3 (though without a clinical primary endpoint, instead it is a change in triglycerides). Two thoughts: first more than 50% of the study subjects were obese; with the evolving standard of care, applicability of future studies will be highly dependent on representative use of GLP-1 agonists. Second, and I have written about this earlier this year, it may be that anything RNAi can do chronically, CRISPR can do better in one-shot. Plozasiran, an RNA Interference Agent Targeting APOC3, for Mixed Hyperlipidemia; Zodasiran, an RNAi Therapeutic Targeting ANGPTL3, for Mixed Hyperlipidemia
Long-acting HIV preexposure prophylaxis (PrEP): it’s about making adherence easy
Daily oral anti-retroviral therapy (ART, e.g. emtricitabine tenofovir disoproxil, aka Truvada) is highly effective for PrEP, but in the real-world, failures occur, probably mostly due to low adherence. Cabotegravir IM (Apretude, ViiV/GSK, approved 2021) is effective, but therapy start is associated with some complexity, and maintenance requires a shot every 2 months, a frequency which is burdensome. In comes lenacapavir from Gilead, a long-acting capsid inhibitor injected subcutaneously (though the 3 ml must be divided in two injections) every 6 months. In a blinded RCT conducted with 5,338 sexually active initially HIV-negative female subjects comparing daily oral ART vs. injected lenacapavir every 6 months, the oral arm registered 55 new cases of HIV, but remarkably the lenacapavir arm registered zero. Additional blood testing of the participants confirmed that by 1 year, adherence with oral therapy was low: the key to success of the injectable was a built-in mechanism for adherence. Twice-Yearly Lenacapavir or Daily F/TAF for HIV Prevention in Cisgender Women
Addressing weight loss in cancer (cachexia)
Unintentional/unexplained weight loss is a finding no primary care physician likes to make because it is frequently the first manifestation of a malignancy. Aside from being a harbinger of cancer, it often eventually leads to muscle loss and outright wasting, decreased ability to engage in activities of daily living, and poor tolerance to treatment regimens such as chemotherapy. There are no approved therapies for cancer cachexia and it has been a neglected unmet need which is why the results from a phase 2 placebo-controlled study showing clear activity of ponsegromab (Pfizer) are exciting. Ponsegromab is an inhibitor of GDF-15, a cytokine which is elevated in ~90% of cancer patients with cachexia (at least as far as I can tell from the disclosed patient screening results). A total of 187 patients were randomized to placebo and 3 regimens of ponsegromab, and there was clear dose-response relationship leading to weight gain, and for the highest dose, increase in muscle by CT evaluation, and increase in physical activity by digital monitoring. Each treatment group was small, and the heterogeneity between cancers and disease advancement was significant so it’s hard to make a full assessment: what is needed is a much bigger trial at a single dose (presumably the highest tested here). But the tea-leaves are favorable that cancer patients will have a new option to address a highly demoralizing problem — looking in the mirror and seeing a skeletal you looking back is very tough. Ponsegromab for the Treatment of Cancer Cachexia
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.