The U.S Food and Drug Administration has approved the expanded use of Mirum Pharmaceuticals' oral drug to treat itching caused by a liver disorder in patients aged five years and older, the company said on Wednesday.
Wednesday, March 13, 2024
David Ricks, CEO of Eli Lilly: A market of over a billion people
Eli Lilly CEO Dave Ricks says GLP-1 is an important invention with the potential to improve the lives of many people and that Lilly has been working in this area for a long time, having launched the first GLP-1 drug in 2005. Although the apparent success of GLP-1 is recent, it is the result of 20 years of work and innovation. He points out that developing real medical breakthroughs takes time and energy, and that metabolic diseases and cancer are far more complex to combat than viral pathogens, such as COVID.
Lilly discovered that higher doses of drugs initially designed to control blood sugar levels could also lead to considerable weight loss. In addition, the combination of two proteins from the incretin family, GLP-1 and GIP (the latter affecting fat metabolism), showed even greater weight loss in mice, while mitigating certain side effects such as nausea.
Following promising results in 2016, Lilly accelerated the development and production of these drugs. However, demand is huge and supply limited. By 2022, Lilly and Novo have produced enough drugs for around 12 million people, a far cry from the one billion obese people reported by the WHO. Lilly is working to increase its production capacity through the construction of new manufacturing facilities, but the complexity of protein manufacturing limits production capacity.
Ricks says that Lilly is working on a solid oral form of the drug that is potentially easier to produce in large quantities. This advance could not only meet demand in the US, but worldwide.
Finally, he discusses Lilly's campaign to destigmatise obesity, which is often perceived as a lack of willpower, but is in fact a serious disease associated with multiple health problems.
Inexperience Diagnosing Syphilis Adding to Higher Rates
With rates of syphilis rising quickly in the United States and elsewhere, clinicians are having to up their game when it comes to diagnosing and treating an infection that they may not be paying enough attention to.
More than 200,000 cases of syphilis were reported in the United States in 2022, which is the highest number since 1950 and is a 17.3% increase over 2021, according to the latest figures from the Centers for Disease Control and Prevention (CDC). The rate of infection has increased almost every year since a historic low in 2001.
And the trend is not limited to the United States. Last year, the infection rate in the United Kingdom hit a 50-year high, said David Mabey, BCh, DM, from the London School of Hygiene and Tropical Medicine. Syphilis and other sexually transmitted infections are also a major problem in low- and middle-income countries, he added, although good data are not always available.
Many of today's healthcare professionals have little experience with the disease, shared Ina Park, MD, a sexually transmitted infections specialist at the University of California at San Francisco. "An entire generation of physicians — including myself — did not see any cases until we were well out of our training," Park reported. "We're really playing catch-up."
A Centuries-Old Ailment
Park offered some advice on the challenges of diagnosing what can be an elusive infection at the Conference on Retroviruses and Opportunistic Infections (CROI) 2024 Annual Meeting in Denver. That advice boiled down to one simple rule: "Test, test, test."
Because syphilis can mimic so many other conditions and can have long periods of latency, it can be easily missed or even misdiagnosed by experienced physicians, said Park. Clinicians need to keep it front of mind and have a lower threshold for testing, even if there are no obvious symptoms.
Following the CDC's new recommendations for syphilis screening will help, she noted; every sexually active patient aged between 15 and 44 years who lives in a county with a syphilis infection rate of 4.6 per 100,000 people or higher should get the test. And clinicians should remain vigilant, even in areas with a lower prevalence. "If you can't account for new symptoms in a sexually active patient, order a test," said Park.
Complicated Cases
The lack of experience with syphilis affects not just diagnosis but also treatment, particularly for complex cases, said Khalil Ghanem, MD, PhD, from the Johns Hopkins University School of Medicine in Baltimore. "When you don't have to deal with something for a while, you forget how to deal with it," he added.
At CROI, Ghanem offered suggestions for how to navigate complicated cases of ocular syphilis, otic syphilis, and neurosyphilis, and how to interpret test results when a patient's antigen titers are being "unruly."
With potential ocular or otic syphilis, you shouldn't wait for a specialist like an ophthalmologist to weigh in but instead refer the patient directly to the emergency department because of the risk that the symptoms may become irreversible and result in permanent blindness or deafness. "You don't want to dilly-dally with those conditions," Ghanem said.
Closely monitoring a patient's rapid plasma regain and venereal disease research laboratory antigen levels is the only way to manage syphilis and to determine whether the infection is responding to treatment, he noted, but sometimes those titers "don't do what you think they should be doing" and fail to decline or even go up after treatment.
"You don't know if they went up because the patient was re-infected, or they developed neurosyphilis, or there was a problem at the lab," he said. "It can be challenging to interpret."
To decipher confusing test results, Ghanem recommended getting a detailed history to understand whether a patient is at risk for reinfection, whether there are signs of neurosyphilis or other complications, whether pregnancy is possible, and so on. "Based on the answers, you can determine what the most rational approach to treatment would be," he shared.
Drug Shortages
Efforts to get the infection under control have become more complicated. Last summer, Pfizer announced that it had run out of penicillin G benzathine (Bicillin), an injectable, long-acting drug that is one of the main treatments for syphilis and the only one that can be given to pregnant people. Supplies for children ran out at the end of June 2023, and supplies for adults were gone by the end of September.
Because Pfizer is the only company that manufactures penicillin G benzathine, there is no one to pick up the slack in the short-term, so the shortage is expected to continue until at least the middle of 2024.
In response, the US Food and Drug Administration has temporarily allowed the use of benzylpenicillin benzathine (Extencilline), a French formulation that has not been approved in the United States, until supplies of penicillin G benzathine are stabilized.
The shortage has shone a spotlight on the important issue of a lack of alternatives for the treatment of syphilis during pregnancy, which increases the risk for congenital syphilis. "Hopefully, this pushes the National Institutes of Health and others to step up their game on studies for alternative drugs for use in pregnancy," Ghanem said.
KUDLOW: Budget numbers could never pass for fiscal responsibility
I want to make a couple comments about the Biden budget. I absolutely love the headline from Reason magazine: "The White House Claims Borrowing $16 Trillion Over the Next Decade Is Fiscally Responsible."
So, that is point number one. Since when is $16 trillion fiscally responsible? Then, the subhead is even better: "If you can't even get close to balancing the budget when unemployment is low, tax revenues are near record highs, and the economy is booming, when can you do it?"
So, that's point number two. Treasury Secretary Janet Yellen – who is a very smart, experienced, and accomplished public servant – was kind of dodging my friend Edward Lawrence today on the issue of tax hikes damaging the economy, falling real worker wages and the problem with all that borrowing, but one generic point I want to make is that the Biden budget doesn't even bother to show balance at the end of the 10-year window.
Not even a phony path to a budget balance. Not even ginning up outrageous growth projections or collapsing interest rates. I mean, the Bidens aren't even good socialists. Here they are touting the efficacy of huge spending and huge tax increases and huge regulatory burdens, but they don't really produce the goods in their own numbers.
I mean, if you really believe this stuff, you should probably show 4-5% economic growth and a balanced budget in 10 years. Heck, even 5 years, but what their budget does show me is they don't believe their policies will actually work.
Of course, I don't believe their policies will work, either. You'd think, if you really bought into the big government socialist model, that you'd build in some good rosy scenarios in the budget, but they don't.
I mean, down through the years, most administrations – in both political parties – show a balanced budget over 10 years. A fiction, yes, but a useful fiction. Even a disciplinary fiction, but not the Bidens. The Biden OMB baseline shows a combined deficit increase of $19.5 trillion and the level of debt in public hands is $28 trillion in FY '24 and $49.8 trillion in FY '34. That's an increase of $22 trillion.
These are gigantic numbers and they could never possibly pass for something called "fiscal responsibility," which is how the Biden factsheet describes their policies. There are no wars. No national emergencies. No pandemic.
No nothing – except record spending and tax revenues, and deficits and borrowing and, of course, no spending cuts to be found. As Reason magazine asks, "If you can't even get close to balancing the budget under those conditions, when can you do it?" That is my question and that if my riff.
Merck KGaA drops BTK inhibitor evobrutinib, marking end of road for blockbuster dreams
It’s been a quick fall from grace for evobrutinib. Only months ago, Merck KGaA was outlining hopes for a major commercialization push for the BTK inhibitor—and now the German pharma has dropped the drug completely.
Merck told Fierce Biotech that the decision was made in response to the failure of evobrutinib to beat Sanofi’s Aubagio in two phase 3 multiple sclerosis (MS) clinical trials in December 2023. With Merck having pinned blockbuster hopes on the drug, the pair of failures sent shockwaves through the BTK inhibitor space at the time.
The company revealed the decision to give up on evobrutinib in a fourth-quarter earnings results presentation, where it described how scrapping the drug came with a one-time cost of 95 million euros ($103.5 million), which Merck booked for the fourth quarter of 2024. This financial impact was counterbalanced by sales momentum and income from the PD-L1 antibody Bavencio, for which Merck re-secured the rights from Pfizer a year ago.
Merck is far from the only Big Pharma to have seen potential in BTK inhibitors to tackle smoldering MS, chronic inflammation linked to the progression of symptoms in patients who appear to have stable disease. Sanofi made a splash in the space by paying $3.7 billion to buy Principia Biopharma in 2020, while Biogen, Novartis and Roche have all taken candidates into phase 2 or 3 clinical trials.
But Merck’s December data removed the German company from the race. Specifically, the annualized relapse rates (ARR) in patients with relapsing MS were almost identical in recipients of evobrutinib and the control drug, Sanofi’s Aubagio.
Responding to the results at the time, Merck noted that the ARRs in recipients of Aubagio were lower than those seen in other recent phase 3 studies of the treatment. The ARR in recipients of evobrutinib slipped from the phase 2 trial, when the rate in patients who received 75 mg twice a day was 0.08 at week 24 and 0.11 in a recent long-term analysis. The ARR on the Aubagio label is 0.37; in another phase 3 trial the ARR was 0.29.
Up to the phase 3 readouts, the company had maintained sky-high hopes for the drug. As recently as November, Merck had outlined plans to support evobrutinib with a major commercialization push, telling investors that launch preparations would drive up costs starting in the fourth quarter and mulling whether to use a voucher to accelerate the FDA review.
On a call with analysts to discuss the earnings results, Merck CEO Belén Garijo admitted the BTK inhibitor’s failure “was no doubt a disappointment.”
“Despite the setback with evobrutinib, we will remain focused on stringent execution of our strategies to both drive our existing product portfolio and to continue to increase optionality for our pipeline,” the CEO added.
Calcitonin gene-related peptide-targeting therapies first-line for migraine prevention: American Headache Society
Abstract
Objective
To provide a position statement update from The American Headache Society specifically regarding therapies targeting calcitonin gene-related peptide (CGRP) for the prevention of migraine.
Background
All migraine preventive therapies previously considered to be first-line treatments were developed for other indications and adopted later for migraine. Adherence to these therapies is often poor due to issues with efficacy and tolerability. Multiple new migraine-specific therapies have been developed based on a broad foundation of pre-clinical and clinical evidence showing that CGRP plays a key role in the pathogenesis of migraine. These CGRP-targeting therapies have had a transformational impact on the management of migraine but are still not widely considered to be first-line approaches.
Methods
Evidence regarding migraine preventive therapies including primary and secondary endpoints from randomized placebo-controlled clinical trials, post hoc analyses and open-label extensions of these trials, and prospective and retrospective observational studies were collected from a variety of sources including PubMed, Google Scholar, and ClinicalTrials.gov. The results and conclusions based upon these results were reviewed and discussed by the Board of Directors of The American Headache Society to confirm consistency with clinical experience and to achieve consensus.
Results
The evidence for the efficacy, tolerability, and safety of CGRP-targeting migraine preventive therapies (the monoclonal antibodies: erenumab, fremanezumab, galcanezumab, and eptinezumab, and the gepants: rimegepant and atogepant) is substantial, and vastly exceeds that for any other preventive treatment approach. The evidence remains consistent across different individual CGRP-targeting treatments and is corroborated by extensive “real-world” clinical experience. The data indicates that the efficacy and tolerability of CGRP-targeting therapies are equal to or greater than those of previous first-line therapies and that serious adverse events associated with CGRP-targeting therapies are rare.
Conclusion
The CGRP-targeting therapies should be considered as a first-line approach for migraine prevention along with previous first-line treatments without a requirement for prior failure of other classes of migraine preventive treatment.
https://headachejournal.onlinelibrary.wiley.com/doi/full/10.1111/head.14692
'Most People With TB Report No Persistent Cough'
A significant proportion of people in the community with pulmonary tuberculosis (TB) have subclinical disease, according to a meta-analysis involving survey studies across Africa and Asia.
In adjusted analyses, 82.8% (95% CI 78.6-86.6) of participants with TB reported no persistent cough and 62.5% (95% CI 56.6-68.7) reported no cough at all, according to Frank Cobelens, MD, MSc, PhD, of the Amsterdam Institute for Global Health and Development, and colleagues from the scTB Meta Investigator Group.
Furthermore, the findings in Lancet Infectious Diseases showed, 27.7% (95% CI 21.0-36.4) of participants with TB reported no symptoms suggestive of the disease at all, including cough, chest pain, fever, night sweats, or weight loss.
"A persistent cough is often the entry point for a diagnosis, but if 80% of those with TB don't have one, then it means that a diagnosis will happen later -- possibly after the infection has already been transmitted to many others -- or not at all," Cobelens said in a press release.
"Our results indicate the probable reason why, despite huge efforts to diagnose and treat the disease, the [TB] burden across Africa and Asia is hardly declining," he added. "It's clear that current practice, especially in the most resource-poor settings will miss large numbers of patients with TB. We should instead focus on x-ray screening and the development of new inexpensive and easy-to-use tests."
The meta-analysis included individual participant data from a dozen surveys conducted in four Asian and eight African nations with high TB incidence over the past 2 decades, ultimately including more 600,000 individuals, 1,944 of whom had TB.
Of the participants with TB, 29.1% (95% CI 25.2-33.3) of those without a persistent cough and 23.1% (95% CI 1.8-27.4) of those without any cough had positive sputum smears, suggesting infectiousness, the study authors noted. The research team also found that TB without cough occurred more frequently among women versus men, though cautioned it's "possible that men with subclinical tuberculosis participated less often in the surveys (e.g., by being away for work)."
The results indicate a "substantial burden" of subclinical disease in nations with high TB prevalence that would be missed under routine case finding, according to Xiaolin Wei, MD, MPH, PhD, of the University of Toronto, and Wenhong Zhang, MD, PhD, of Fudan University in Shanghai. They added that subclinical TB represents an "imminent challenge" to the World Health Organization's goal of ending tuberculosis by 2035.
"These findings call for revisiting the definition of tuberculosis-suggestive symptoms that warrant clinical investigation," the pair noted in an invited comment, though cautioned that changes in national guidelines would need to be balanced against the capacities of TB programs.
"Unlike preventive tuberculosis treatment, management of subclinical tuberculosis needs to be given full legal and public health consideration, because subclinical tuberculosis contributes to tuberculosis transmission," wrote Wei and Zhang. "However, subclinical tuberculosis management is challenging, as patients tend to be less motivated for treatment and less likely to adhere to their regimens given their absence of or minimal symptoms. Digital adherence tools, such as tools on mobile applications or electronic medical monitors, could be helpful."
In the U.S., more than 8,000 cases of the deadly infection were reported in 2022, a 5.9% increase versus the prior year, according to the CDC, and an estimated 13 million people are living with latent infections.
Reynold Panettieri Jr., MD, of the Rutgers Institute for Translational Medicine and Science in New Brunswick, New Jersey, who was not involved in the study, said that individual factors such as a patient's immune status or even nutrition can play a role in how TB symptoms manifest.
"There are people who are immune-compromised where the infection could continue, but not cause, many symptoms because their immune system isn't fighting the infection," he told MedPage Today. "They're infectious, their cough or sneezing may bring up tuberculin, but they may not have had symptoms because they have no inflammation."
Panettieri encouraged frequent TB testing through purified protein derivative (PPD) skin testing or blood testing when suspicion arises, particularly following direct exposure or if a patient is immunocompromised.
Study Details
Data from the analysis came from 12 of 31 eligible nationally representative surveys conducted in Cambodia, Ghana, Laos, Lesotho, Nigeria, Pakistan, South Africa, Sudan, Gambia, Uganda, Vietnam, and Zambia that reported pulmonary TB prevalence and symptom screening from 2007 to 2020. Studies that primarily included children, pregnant people, people living with HIV, incarcerated people, migrants, and household contacts of TB patients were excluded.
A majority of the 602,863 participants were from Africa, 57.6% were women, nearly 60% lived in rural areas, and roughly half were under the age of 35. TB screening was conducted via chest x-ray, while symptoms were self-reported. Screening and diagnostic criteria were standardized across the surveys, and TB was defined by positive sputum culture.
Models adjusted for age, sex, and urban versus rural settings, as well as for incomplete sensitivity of x-ray screenings and missing or contaminated cultures.
The researchers examined three definitions of subclinical disease:
- No persistent cough: positive sputum culture but no cough lasting 2 weeks or more prior to screening
- No cough: positive culture but no cough of any duration
- No symptoms: positive culture but no cough, fever, chest pain, night sweats, or weight loss
Cobelens and co-authors stressed that the primary study limitation was that the regression models used did not account for "HIV status, smoking, or indicators of socioeconomic status, because these data were not available for all surveys." They also noted the small number of surveys ultimately used in the analysis.
Disclosures
The study was supported by the Mr Willem Bakhuys Roozeboom Foundation.
Cobelens and co-authors, as well as Panettieri, disclosed no relationships with industry.
Wei and Zhang declared no competing interests.
Primary Source
The Lancet Infectious Diseases
Source Reference: Stuck L, et al "Prevalence of subclinical pulmonary tuberculosis in adults in community settings: an individual participant data metaanalysis" Lancet Infect Dis 2024; DOI:10.1016/ S1473-3099(24)00011-2.
Secondary Source
The Lancet Infectious Diseases
Source Reference: Wei X, Zhang W “The hidden threat of subclinical tuberculosis” Lancet Infect Dis 2024; DOI:10.1016/S1473-3099(24)00069-0.
https://www.medpagetoday.com/pulmonology/tuberculosis/109146
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