The best single episode of any podcast (subscribe to 70) that I have heard this year. The episode is so good, I will probably repost this message a couple times in 2025.

“In 1962, President John F. Kennedy said, “Those who make peaceful revolution impossible will make violent revolution inevitable.”

It was a recognition of a universal truth in human history: Social stability, the rule of law, and civilization will eventually break down if a population is immiserated for too long while a handful of elites profit. And just two months after that speech, Kennedy honed in on the health care crisis in America, pressing for the passage of what would become Medicare. ”

“What we are now talking about doing, most of the countries of Europe did years ago,” he said at a Madison Square Garden rally. “We are behind every country, pretty nearly, in Europe, in this matter of medical care for our citizens.”

I’ve been thinking a lot about that moment in history in light of the news over the past week. All of a sudden, after the murder of UnitedHealthcare CEO Brian Thompson, everyone is talking about health care, even though almost nobody was talking about it during the presidential campaign.

David Sirota reflects on the shocking murder of United Health CEO Brian Thompson and the surge of public anger it unleashed against America’s broken health insurance system. Why hasn’t this longstanding outrage translated into universal health care — a system every other wealthy nation already has?

Tracing decades of broken promises and corporate influence — from the Clinton and Obama administrations to today — Sirota looks at how political corruption has trapped Americans in a system that profits from their suffering. Drawing on JFK’s 1960s warnings about social stability and justice, this audio essay explores the health care crisis as a symptom of a deeper democracy crisis — and asks what it will take for Americans to finally demand change.

https://podbay.fm/p/lever-time/e/1734429600

Parkinson’s Disease

• Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease. Performed market assessment for some of the latest (2024) treatments for PD. (1) Produodopa—a new treatment approved by NICE for people with PD who experience movement-related symptoms. It’s delivered continuously by a small pump that’s inserted under the skin. (2) Vyalev—(foscarbidopa and foslevodopa) is a solution of carbidopa and levodopa prodrugs for 24-hour continuous subcutaneous infusion that’s been approved for PD motor fluctuations. (3) Crexont—a new formulation of immediate- and extended-release levodopa with carbidopa. (Levodopa is converted in the brain to dopamine, the chemical that goes missing in PD; carbidopa helps levodopa get into the brain and decreases side effects.) (4) Safinamide— a novel experimental drug that shows potential in the treatment of PD and epilepsy. It works by blocking voltage-dependent sodium and N-type calcium channels, inhibiting glutamate release. (5) Methylphenidate and atomoxetine—noradrenaline reuptake inhibitors that are being investigated for their effects on balance and gait. (6) Levodopa inhalation powder—a formulation of levodopa that can be used as needed when medication effects wear off. (7) Focused ultrasound—a minimally invasive treatment that uses beams of heat to generate acoustic energy and precisely target areas of the brain that control voluntary movement. (8) Deep brain stimulation—a surgical procedure that involves implanting electrodes in the brain to deliver electrical impulses and disrupt abnormal circuitry. (9) Bemdaneprocel—a cell therapy that’s showing positive results in clinical trials, including improved motor function and symptom control.
• ASPIRO Clinical Trial (Phase 1 & 2a). Autologous dopamine neuron progenitor cells (DANPCs) are surgically implanted into the putamen of patients with PD. The putamen is a round structure located at the base of the forebrain (telencephalon). The putamen and caudate nucleus together form the dorsal striatum. The putamen is a subcortical structure that is part of a group of structures known as the basal ganglia or basal nuclei. (“Basal nuclei” is technically more accurate, because “ganglia” usually refers to clusters of nerve cell bodies outside the central nervous system.) The putamen is adjacent to the globus pallidus and together they are sometimes referred to as the lentiform or lenticular nucleus. The putamen is involved in (reward-related) learning and motor control, including speech articulation, language functions, reward, cognitive functioning, and addiction.
  • PD affects the putamen in several ways, including Dopamine depletion—PD causes a gradual loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), which leads to a depletion of dopamine in the putamen. This depletion causes motor dysfunction. Atrophy—the putamen can undergo atrophy, which is associated with motor symptoms and cognitive status.  Shape changes—The putamen can undergo shape changes, particularly in the right putamen. Decreased activity.

• Other parts of the brain that are affected by PD include the caudate and nucleus accumbens, which can also experience dopamine depletion. Dopamine replacement therapy can partially restore motor function, but long-term treatment can lead to motor complications.
• The effect on PD symptoms, safety and tolerability, and cell survival are assessed for 5 years post-transplant (with MRI and PET imaging scans of the brain). Safety and tolerability are assessed annually for an additional 10 years via telephone call (total follow-up of 15 years).
• The biologic implanted, ANPD001, is an experimental product derived from autologous skin cells converted to induced pluripotent stem cells. The stem cells were differentiated into DANPCs. Dose escalation will be achieved by bilateral injection of these DANPCs into the putamen.
• Primary outcome measures: incidence and severity of treatment emergent adverse events (TEAE) and serious adverse events. Secondary outcome measures: “ON” time without troublesome dyskinesia [Time Frame: 1 year (primary follow up) and 5 years (long term follow up)]. Post-injection change in Movement Disorder Society – Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part II (Activities of Daily Living – ADL) and Part III (motor score) in the ON state. “ON” time or ON state simply means the period when the Parkinson’s medication is effectively managing symptoms, allowing for normal movement with minimal side effects.
•  The anterior commissure (AC) is a bundle of nerve fibers that connects different parts of the brain and is important for communication between the brain and the body. The AC is a white matter tract that connects the two cerebral hemispheres across the midline, in front of the fornix columns. Although PD is primarily considered a gray matter (GM) disease, alterations in white matter (WM) have gained increasing attention in PD research recently. Recent evidence from MRI scans reveals correlations between WM changes and specific PD symptoms, and these WM abnormalities may be caused by changes of oligodendrocyte (OLs)/myelin in PD.

https://biomedres.us/pdfs/BJSTR.MS.ID.009118.pdf 

https://www.researchgate.net/publication/383861594_An_Independent_Review_of_Camrelizumab-Rivoceranib_Combination_Therapy_for_the_Treatment_of_Hepatocellular_Carcinoma_and_Rivoceranib_for_Gastric_Cancer/

Abstract: The CARES-310 clinical trial compared the safety and efficacy of camrelizumab, an anti-PD-1 antibody, combined with rivoceranib, a vascular endothelial growth factor receptor 2 (VEGFR2)-targeted tyrosine kinase inhibitor (TKI), versus the obsolete standard of care sorafenib as first-line (1L) treatment for unresectable hepatocellular carcinoma (uHCC). In this independent analysis of the CARES-310 trial, potential bias in the choice of comparator and the clinical significance of the results are reexamined. Although rivoceranib (also known as “apatinib”) is approved in China to treat patients with advanced gastric cancer, the clinical trial conducted in the USA for patients with gastric cancer seems to indicate missed endpoints and weak evidence to justify FDA approval. Due to a nondisclosure agreement, the principal investigators are unable to comment on these results. However, from a table of functional benefits and harms, readers might well conclude that palliative hospice care is non-inferior to rivoceranib for patients with Stage 4 gastric cancer.

https://biomedres.us/pdfs/BJSTR.MS.ID.009118.pdf

Conclusion

The CARES-310 clinical trials produced a new longest median OS of 23.8 months for patients with uHCC treated with C-R.  However, the CARES-310 clinical trial may have been overweighted with an Asian population with preexposure to antiviral therapy and better preservation of liver function at time of HCC diagnosis. Conversely, the CARES-310 trial was underweighted with Western patients who have NAFLD, diabetes, obesity, and other co-morbidities and confounding factors.  Oncologists already have 1L patient treatment experience for uHCC with Roche’s FDA-approved anti-PD-L1/VEGF combination Tecentriq and Avastin and with AstraZeneca’s CTLA-4 checkpoint inhibitor Imjudo combined with its PD-L1 antagonist Imfinzi for treatment of uHCC. It would be useful to compare the C-R proposed therapy with these drug combinations and determine if C-R maintains an 8.6-month median OS advantage over the new comparator(s).

When rivoceranib plus hospice care was compared to hospice care alone in a clinical trial of patients with advanced gastric cancer or gastroesophageal adenocarcinoma, the results data were mixed. For some measures of functional benefits and harms, the patients with hospice care alone had higher percentages for certain functional benefits and lower percentages for some harms and adverse events.  The rivoceranib-treated group failed to consistently outperform hospice care alone using these measures.  Based on those benefits and harms, hospice care alone was not inferior to rivoceranib + hospice care, which calls into question the underlying clinical value, if any, of rivoceranib to the American patient population with advanced gastric cancer.  The fact that rivoceranib, known as apatinib, is approved in China for treatment of advanced gastric raises anew questions about fundamental differences in patient populations between China and the USA or Europe for medical conditions such as uHCC and advanced gastric cancer.

References

1. Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ. 2003 May 31;326(7400):1167-70. (“Systematic bias favours products which are made by the company funding the research. Explanations include the selection of an inappropriate comparator to the product being investigated and publication bias.”)
2. Sismondo S. Epistemic Corruption, the Pharmaceutical Industry, and the Body of Medical Science. Front Res Metr Anal. 2021 Mar 8;6:614013 (“Put simply, if a pharmaceutical company funds a trial, the chances of results and conclusions in that company’s favor are increased.”)
3. Bradley SH, DeVito NJ, Lloyd KE, Richards GC, Rombey T, Wayant C, Gill PJ. Reducing bias and improving transparency in medical research: a critical overview of the problems, progress and suggested next steps. J R Soc Med. 2020 Nov;113(11):433-443 (“[A]voidable methodological failings and biases lead to ‘research waste’, which is estimated to account for 85% of all medical research funding.”)
4. Sismondo S (2007) Ghost Management: How Much of the Medical Literature Is Shaped Behind the Scenes by the Pharmaceutical Industry? PLoS Med 4(9): e286. https://doi.org/10.1371/journal.pmed.0040286[1]
5. Mann H, Djulbegovic B. Comparator bias: why comparisons must address genuine uncertainties. J R Soc Med. 2013 Jan;106(1):30-3.
6. Setoguchi S, Gerhard T. Comparator Selection. In: Velentgas P, Dreyer NA, Nourjah P, et al., editors. Developing a Protocol for Observational Comparative Effectiveness Research: A User’s Guide. Rockville (MD): Agency for Healthcare Research and Quality (US); 2013 Jan. Chapter 5. Available from: https://www.ncbi.nlm.nih.gov/books/NBK126184/
7. Pinato DJ, D’Alessio A, Celsa C, Manfredi GF, Fulgenzi CAM. The price and value of therapeutic synergy in liver cancer. Lancet. 2023 Sep 30;402(10408):1108-1110.
8. Lee, W.S., Yang, H., Chon, H.J. et al. Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity. Exp Mol Med 52, 1475–1485 (2020). https://doi.org/10.1038/s12276-020-00500-y
9. Qin S, Chan SL, Gu S, et al., CARES-310 Study Group. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study. Lancet. 2023 Sep 30;402(10408):1133-1146.
10. Supplement to: Qin S, Chan SL, Gu S, et al. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study. Lancet 2023; published online July 24. https://doi.org/10.1016/S0140-6736(23)00961-3.
11. Wang, F., Qin, S., Sun, X. et al. Reactive cutaneous capillary endothelial proliferation in advanced hepatocellular carcinoma patients treated with camrelizumab: data derived from a multicenter phase 2 trial. J Hematol Oncol 13, 47 (2020).
12. Liu Y, Chen T, Zhang C, Pan W. Emerging Treatments for Reactive Cutaneous Capillary Endothelial Proliferation. Indian J Dermatol. 2023 Jan-Feb;68(1):85-90.
13. Vogel A., Chan SL, Ren Z et al. Camrelizumab plus rivoceranib vs sorafenib as first-line therapy for unresectable hepatocellular carcinoma (uHCC): Final overall survival analysis of the phase 3 CARES-310 study. Journal of Clinical Oncology 42(16_suppl) https://doi.org/10.1200/JCO.2024.42.16_suppl.4110.
14. Li, J., Qin, S., Wen, L. et al.Safety and efficacy of apatinib in patients with advanced gastric or gastroesophageal junction adenocarcinoma after the failure of two or more lines of chemotherapy (AHEAD): a prospective, single-arm, multicenter, phase IV study. BMC Med 21, 173 (2023). https://doi.org/10.1186/s12916-023-02841-7
15. Liu, Angus, “FDA snubs another China-made PD-1 with rejection of Elevar, Hengrui’s liver cancer combo,” Fierce Pharma. 2024 May 17.https://www.fiercepharma.com/pharma/fda-pd-1-combo-elevar-hengrui-camrelizumab-liver-cancer
16. Kansteiner, Fraiser, “Elevar commits $600M-plus to take Hengrui’s liver cancer cocktail to market in US and beyond,” Fierce Pharma. 2023 Oct 17. https://www.fiercepharma.com/ pharma/elevar-ponies-600m-take-hengruis-investigational-liver-cancer-cocktail-market-us-and-beyond
17. Elevar Therapeutics, “Elevar Therapeutics Reports Plans for Near-Term Resubmission of NDA for First-Line Treatment Option for Unresectable Hepatocellular Carcinoma Following Type A FDA Meeting,” Press Release. 2024 Jul 9. https://elevartherapeutics.com/2024/07/09/ elevar-therapeutics-first-line-treatment-option/
18. Liu, Angus, “UPDATED: Elevar, Hengrui eye accelerated refile for PD-1 liver cancer combo after surprise FDA rejection” Fierce Pharma. 2024 Jul 12. https://www.fiercepharma.com/ pharma/elevar-hengrui-eye-quick-refile-pd-1-liver-cancer-combo-after-surprise-fda-rejection

Acknowledgments

Christopher Coleman, Pharm.D., provided useful comments.

Conflict of Interests

None.

In the obesity landscape, glucagoon-like peptide-1 (GLP-1) agonists dominate the weight loss market. Amylin agonists work differently from GLP-1s but may be able to induce similar weight loss with fewer adverse events. My client wanted to understand the molecular differences between various amylin assets and their hypothetical impacts on the efficacy / adverse event profile.

Project’s key research questions/topics include:
(1) Describe the medical literature as it pertains to Amylin for obesity specifically – e.g. years researching, articles on Amylin published, clinical trials, or other types of experience – please specify.

(2) Comment on the differences between cagrilintide, petrelintide, amycretin and any other amylin agonists?

(3) Describe the theoretical physiologies of the various subsets within amylin receptors (calcitonin, AMY1R, AMY2R, AMY3R).

(4) Comment on whether the pH of the assets differ, and whether these could have material impacts on the drug profile?

(5) Comment on the solubility of cagrilintide and other amylin assets, as well as the corresponding impacts on the drug profile (e.g. half-life)?

Despite the similarities between GLP-1 and Amylin agonists (e.g. both molecular classes slow gastric emptying, decrease glucagon, and inhibit food intake), there are important distinctions between the central and/or peripheral pathways that mediate their effects on hyperglycemia and energy balance.

Pictures shot by Heather Cox Richardson while kayaking.