The drug has been in short supply since at least August, an issue that
Friday, October 7, 2022
Teva Sees Adderall Supply Delays Continuing for 2-3 Months
FDA Review: Alnylam, Cytokinetics, Eli Lilly and More (Oct. 3 week)
The FDA had a fairly quiet week, approving drugs, providing clearance, greenlighting clinical trials, and other regulatory activities for Alnylam, Eli Lilly, Cytokinetics, Prometheus, Owlet, and more.
Here’s a look at the agency’s reported activities.
Oct. 6
Alnylam Pharmaceuticals’ Oxlumo (lumasiran) received an approval for an expanded indication to include advanced primary hyperoxaluria type 1 (PH1) patients with severe renal impairment, including patients on hemodialysis.
The FDA scheduled a Cardiovascular and Renal Drugs Advisory Committee meeting for Dec. 13 to discuss Cytokinetics’ NDA for omecamtiv mecarbil tablets to reduce the risk of cardiovascular death and heart failure events in patients with symptomatic chronic heart failure with reduced ejection fraction.
Eli Lilly received Fast Track designation for its tirzepatide to treat adults with obesity or overweight with weight-related comorbidities.
Boston Cell Standards received 510(k) clearance for its IHControls panel (HER2/ER/PR) for evaluating breast cancers.
Owlet submitted a 510(k) premarket notification for a new prescription monitoring device for infants. The device uses pulse oximetry and is intended to be prescribed by doctors for in-home monitoring of babies.
Annovis Bio received the go-ahead for a Phase II/III trial of buntanetap in moderate Alzheimer’s.
Entera Bio concluded its Type C meeting and agreement with the FDA that a single Phase III placebo-controlled trial could support an NDA of EB613 under the 505(b)(2) regulatory pathway. The FDA also agreed that Total Hip Bone Mineral Density (BMD) could be the primary endpoint of the registrational trial in post-menopausal osteoporosis patients.
Kiromic BioPharma received validating written feedback from the FDA regarding its Type B Pre-IND meeting request over its Deltacel development strategy. Deltacel/KB-GDT is being developed for non-small cell lung cancer.
Oct. 5
Transcenta Holding’s TST004 received IND clearance to run a clinical trial for the treatment of IgA nephropathy.
Oct. 4
Multi Radiance Medical received FDA clearance for its MRM FibroLux laser therapy to treat pain associated with fibromyalgia.
Oct. 3
PDS Biotechnology reported a successful End-of-Phase II meeting with the FDA for PDS0101 in combination with Merck’s Keytruda for treatment of unresectable, recurrent/metastatic human papilloma virus (HPV) 16-positive head and neck squamous cell carcinoma (HNSCC). PDS will move into a registrational trial ahead of the originally planned schedule.
Prometheus Biosciences received the greenlight to initiate a Phase I single ascending dose/multiple ascending dose (SAD/MAD) trial for PRA052 in healthy volunteers. The drug is being developed to treat ulcerative colitis.
Kira Pharmaceuticals received clearance to launch a Phase II trial of KP104 in systemic lupus erythematosus associated thrombotic microangiopathy.
Kite announced the FDA approved its retroviral vector (RVV) manufacturing facility in Oceanside, Calif.
Eagle Pharmaceuticals’ ENA-001 was granted Orphan Drug Designation for treatment of Apnea of Prematurity.
Poxel received Orphan Drug Designation for PXL770 for patients with autosomal-dominant polycystic kidney disease.
Seneca Therapeutics received clearance to initiate a Phase I/II trial using Seneca Valley Virus (SVV-001) in combination with a checkpoint inhibitor in patients that are TEM8 positive and SVV-001 permissive with neuroendocrine tumors of neuroendocrine carcinomas.
Sept. 30
Taiho Oncology and Taiho Pharmaceutical Co.’s Lytgobi was approved by the FDA for treatment of adults with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma harboring FGFR2 gene fusions or other rearrangements.
https://www.biospace.com/article/fda-review-alnylam-cytokinetics-eli-lilly-and-more/
Fresenius taps pre-dialysis kidney care as drugs promise treatment change
The world’s largest dialysis company is seeking out kidney disease patients long before they need the most acute form of care as it plans for growth of new drugs that attack the condition’s causes early on.
For decades, Germany’s Fresenius Medical Care (NYSE:) (FMC (NYSE:)) has been the biggest player in the $50 billion U.S. market providing dialysis and related machines that help filter out blood toxins for people whose kidneys have failed to function.
The company’s 17.6 billion euros ($17.6 billion) in annual revenue has been sustained for decades by high rates of obesity and diabetes, which contribute to kidney damage.
But the dialysis market is changing as new medications have been shown to dramatically improve the conditions that lead to kidney failure.
FMC anticipates that the introduction of these drugs could be a drag on its patient population growth for at least some years. To diversify its revenue base it is pushing to expand beyond its core dialysis business into the care of earlier stage kidney disease.
The new drugs include AstraZeneca (NASDAQ:)’s Farxiga diabetes pill that also delivers benefits for non-diabetics as an approved treatment to slow chronic kidney disease (CKD).
Germany’s Boehringer Ingelheim and Eli Lilly (NYSE:)’s Jardiance diabetes drug is expected to be used for the same purpose, while Novo Nordisk (NYSE:)’s Wegovy injection offers a new treatment option for obesity. Other similar new treatments such as Eli Lilly’s Mounjaro are also expected to offer new weight loss options.
They all add pressure to the dialysis industry which faces rising costs and a temporary shrinking of its patient pool, particularly in the United States.
More than 15,000 people on dialysis are estimated to have died of COVID in 2020 alone, according to the U.S. Renal Data System. A labour shortage in the U.S. healthcare market has pushed wages higher and forced FMC, which derives about 70% of its revenue from the United States, and other dialysis providers to rely more on temporary staff.
A U.S. Supreme Court ruling has also shifted how much kidney care coverage private insurers and the government must offer.
The pressures have pushed FMC’s shares to a near 13-year low and analysts expect the company’s adjusted net income to decline 14.5% to 870 million euros this year.
Parent company Fresenius SE (ETR:) has said a sale of FMC could not be ruled out.
For now though, FMC is trying to reposition itself in the market and sees hope for the company and patients alike: the new drugs, by slowing the progression of disease, should prolong the lives of those who do eventually need dialysis, keeping patients in FMC’s care for longer, Frank Maddux, FMC’s global chief medical officer, told Reuters.
“In the short run, we’ll see the impact of some delayed (chronic kidney disease) progression but in the longer run, we’re probably going to see an expansion of the number of people with chronic kidney disease that survive to live with the disease,” said Maddux.
Sabastien Buch, a fund manager at Union Investment in Frankfurt, Germany, which holds FMC shares, agreed that even if fewer people end up needing dialysis, those who do are likely to live longer, thanks to the new drugs.
“Patients that start dialysis in better health will not pass away after four or five years, but will be part of a group that remain on therapy for maybe seven or eight years, which are rather rare cases today,” said Buch.
DOCTORS BACK NEW DRUGS
FMC’s expansion into earlier care includes services that will integrate the new drugs, and the company says it plans to capitalize on a growing trend in which health insurers reward care providers financially for keeping patients in good health.
In March it purchased Cricket Health, one of several U.S. companies that specialize in managing kidney patient care.
FMC said the new kidney care market it is targeting is worth $120 billion. The company’s closest rival, Davita has said it is also trying to expand in the market. It did not respond to requests for comment.
Daniel Grigat, an analyst at brokerage Stifel, said the drugs could reduce growth in FMC’s traditional dialysis business in the United States and Europe by 20% in the next five to 10 years depending on how quickly the use of drugs picks up.
However, growth in emerging markets, where the drugs are not expected to be widely used, could offset half of the decline in U.S. and European sales, he said.
FMC declined to give specific estimates about the drugs’ impact on its sales.
While use of AstraZeneca’s Farxiga has been limited so far, Farxiga and potentially Jardiance are expected to be used more widely as their benefits become more appreciated and if U.S. insurers lower barriers to use, doctors said.
It is not yet known to what extent these and the obesity drugs will prevent people from needing dialysis altogether.
Drugs like Farxiga reduce the risk of progressing to kidney failure about 40% of the time, said nephrologist Katherine Tuttle, a professor at the University of Washington in Seattle. Current drugs are less effective, and are also prescribed only to a minority of patients, she said.
Anjay Rastogi, director of the University of California at Los Angeles kidney health programme, said “every one” of his patients who is eligible is being prescribed drugs like Farxiga or Jardiance that are known as SLGT2 inhibitors.
LOWER COSTS
By delaying the onset of kidney failure, such drugs will decrease health spending in the long run, says Phil McEwan, a predictive modelling expert and chief executive of health economics consultancy Heor Ltd. based in Cardiff, Wales.
Monthly U.S. spending per dialysis patient was over $14,000, or 33 times more than on those without end-stage renal disease, according to University of Southern California research based on 2016 data.
Farxiga’s list price is around $500 per month, though it may be less with discounts.
McEwan and Dan Lyons, who manages healthcare-focused funds at Janus Henderson Investors in Denver, Colorado, said trial results expected later this year on the cardiovascular benefits from losing weight while taking Wegovy will likely boost prescriptions of that drug.
Wegovy has already been shown to help overweight people shed 35 pounds or more.
“The growth rate in dialysis patients is probably not what was anticipated 10 years ago when we didn’t see these drugs,” said FMC’s Maddux. “We saw a steeper curve than what we now think it probably will be.”
Walgreens, Walmart To Start Selling OTC Hearing Aids By Oct. 17
Major U.S. pharmacy operators Walgreens Boots Alliance (NASDAQ:) and Walmart (NYSE:) Inc said on Thursday that in mid-October they would start selling hearing aids over-the-counter without the need for a medical exam, prescription, or audiologist fitting.
The companies are rolling out the products across the nation after the U.S. Food and Drug Administration in August issued a rule easing access to hearing aids for millions of Americans with mild to moderate hearing loss.
The rule, which goes into effect this month, should make it easier to buy lower-priced models.
Walgreens said it was planning to make Lexie Lumen hearing aids available at its stores across the country for adults starting Oct. 17 at a price of $799.
Walmart separately told Reuters it would begin offering hearing aids to adults with mild to moderate hearing loss without an assessment or medical exam by Oct. 17.
Products would start at $200 and will be available at Walmart.com and its vision centers.
Prior to allowing over-the-counter sale, these devices were only available at hearing centers and typically cost thousands of dollars. According to White House estimates, the change is expected to save consumers about $2,800 per pair.
In a statement to Reuters, CVS Health (NYSE:) said it currently has a limited selection of hearing aids available on CVS.com, and it “plans to add to these offerings and expand to retail stores in the near future.”
Hearing aids for severe hearing loss or for users below 18 years of age remain as prescription devices.
EPA Proposes to Declare Aviation Lead Emissions Public Health Danger
The U.S Environmental Protection Agency (EPA) on Friday said it was proposing to declare emissions from piston-engine aircraft operating on leaded fuel pose a danger to public health.
Emissions from the 190,000 U.S. general aviation airplanes operating on leaded fuel account for about 70% of the lead entering the atmosphere, according to U.S. government estimates. Lead is not in jet fuel, which is used by commercial aircraft.
The EPA said if the proposed "endangerment finding" is finalized, it would subsequently propose regulatory standards for lead emissions from aircraft engines.
Reuters first reported in January that the EPA was again reviewing whether emissions from piston-engine aircraft operating on leaded fuel contribute pose a danger to public health.
While levels of airborne lead in the United States have declined 99% since 1980, piston-engine aircraft are the largest remaining source of lead emissions into the air.
Children's exposure to lead can cause irreversible and lifelong health effects, the EPA said.
"When it comes to our children, the science is clear, exposure to lead can cause irreversible and life-long health effects,” EPA Administrator Michael Regan said in a statement on Friday. "Aircraft that use leaded fuel are the dominant source of lead emissions in the country."
In 2006, the EPA received a petition asking for regulations of lead emissions from general aviation airplanes. The agency opened a proceeding in 2010 to review the issue and in 2015 said it had planned to issue a final endangerment finding in 2018.
The majority of aircraft that operate on leaded aviation gasoline are small piston-engine aircraft that typically carry two to 10 passengers.
The Federal Aviation Administration in February announced a new initiative outlining how to safely eliminate the use of leaded aviation fuel by the end of 2030 without adversely affecting the existing piston-engine fleet.
Pumping Iron Improves Longevity in Older Adults
Older adults who take part in regular weightlifting — either with or without moderate to vigorous aerobic activity — show significant reductions in all-cause and cardiovascular disease (CVD) mortality, with the strongest effects observed when the two types of exercise are combined, new research shows.
"The novel finding from our study is that weightlifting is independently associated with lower all-cause and CVD-specific mortality, regardless of aerobic activity," first author Jessica Gorzelitz, PhD, told Medscape Medical News.
"What's less surprising — but consistent and nonetheless noteworthy — is that weightlifting in combination with aerobic exercise provides the lowest...risk for mortality in older adults," added Gorzelitz, an assistant professor of health promotion in the Department of Health and Human Physiology at the University of Iowa in Iowa City.
Those who undertook weightlifting and aerobic exercise in combination had around a 40% lower risk of death than those who reported no moderate to vigorous aerobic activity or weightlifting. The findings were recently published online in the British Journal of Sports Medicine.
Physical activity guidelines generally recommend regular moderate to vigorous aerobic physical activity, in addition to at least 2 days per week of muscle-strengthening exercise for all major muscle groups for adults to improve health and boost longevity.
However, few observational studies have examined the association between muscle strengthening and mortality, and even fewer have looked specifically at the benefits of weightlifting, Gorzelitz said.
Benefit of Weightlifting Stronger in Women Than Men
To investigate, Gorzelitz and coauthors evaluated data on participants in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, which, initiated in 1993, and involved adults aged 55-74 at 10 US cancer centers.
Thirteen years into the trial, in 2006, participants completed follow-up questionnaires that included an assessment of weightlifting (not included in a baseline survey).
Among 99,713 participants involved in the current analysis, the mean age at the time of the follow-up questionnaire was 71.3 years. Participants had a mean body mass index (BMI) of 27.8 kg/m2 and 52.6% were women.
Only about a quarter of adults (23%) reported any weightlifting activity within the previous 12 months, with fewer, at 16%, reporting regular weightlifting of between one and six times per week.
Participants' physical aerobic activity was also assessed. Physical activity guidelines (2018) recommend at least 150-300 minutes per week of moderate-intensity aerobic physical activity or 75-150 minutes per week of vigorous intensity aerobic activity or an equal combination of the two. Overall, 23.6% of participants reported activity that met the guideline for moderate to vigorous physical activity, and 8% exceeded it.
Over a median follow-up of about 9 years, 28,477 deaths occurred.
Those reporting weightlifting had a 9% lower risk of combined all-cause mortality and CVD mortality, after adjustment for any moderate to vigorous physical activity (each hazard ratio [HR], 0.91).
Adults who met aerobic activity recommendations but did not weightlift had a 32% lower risk of all-cause mortality (HR, 0.68), while those who also reported weightlifting 1-2 times per week in addition to the aerobic activity had as much as a 41% lower risk of death (HR, 0.59) compared with adults reporting no moderate to vigorous aerobic activity or weightlifting.
The benefit of weightlifting in terms of cancer mortality was only observed without adjustment for moderate to vigorous physical activity, and was therefore considered null, which Gorzelitz noted was somewhat surprising. "We will examine this association further because there could still be a signal there," she said, noting other studies have shown that muscle strengthening activity is associated with lower cancer-specific mortality.
Of note, the benefit of weightlifting appeared stronger in women versus men, Gorzelitz said.
What Are the Mechanisms?
Underscoring that the results show only associations and not causation, Gorzelitz speculated that mechanisms behind a mortality benefit could include known favorable physiological changes of weightlifting.
"If people are weightlifting [to a degree] to reap strength benefits, we generally see improvement in body composition, including reductions in fat and improvements in lean tissue, and we know that those changes are associated with mortality, so it could be that the weightlifting is driving the strength or body composition," she said.
The full body response involved in weightlifting could also play a key role, she noted.
With weightlifting, "the muscles have to redirect more blood flow, the heart is pumping harder, the lungs breathe more and when the muscles are worked in that fashion, there could be other system-wide adaptations," she said.
Furthermore, social aspects could play a role, Gorzelitz observed.
"Unlike muscle strengthening [activities] that can be done in the home setting, weightlifting typically has to be done in recreational facilities or other community centers, and considering that this is an older adult population, that social interaction could be very key for preventing isolation."
Important limitations include that the study did not determine the nature of the weightlifting, including the duration of the weightlifting sessions or type of weight, which could feasibly range from small hand-held weights to heavier weightlifting.
The study also couldn't show how long participants had engaged in weightlifting in terms of months or years, hence, the duration needed to see a mortality benefit was not established.
Nevertheless, the study's finding that the group with the lowest benefits was the one reporting no aerobic or weightlifting exercise underscores the benefits of even small amounts of exercise.
"I think it's really important to promote the importance of adding muscle strengthening, but also of any physical activity," Gorzelitz said. "Start small, but something is better than nothing."
The authors have reported no relevant financial relationships.
Br J Sports Med. Published online September 27, 2022. Abstract
Emerging Invasive Fungal Infections Call for Better Records
Emerging invasive fungal infections represent a new diagnostic and therapeutic challenge. To address their growing clinical impact on immunocompromised patients requires better local epidemiologic records, said a specialist at the XXII Congress of the Argentine Society of Infectology (SADI 2022).
"To know that these fungal infections exist, we need epidemiologists, doctors, and microbiologists to join in constant and ongoing multidisciplinary work to generate the necessary databases and to know the pathologies that we have. I believe that in this respect we are falling short," said Javier Afeltra, PhD, a mycologist at the Ramos Mejía Hospital in Buenos Aires, professor of microbiology at the School of Medicine of the University of Buenos Aires, and coordinator of the commission of immunocompromised patients of the Argentine Society of Infectious Diseases.
"There is some change in mentality that encourages professionals to report the cases they detect ― for example, in scientific meetings," Afeltra told Medscape Spanish Edition. "But the problem is that there is no unified registry.
"That's what we lack: a place to record all those isolated cases. Records where clinical and microbiological data are together within a click. Perhaps the microbiologists report their findings to the Malbrán Institute, an Argentine reference center for infectious disease research, but we do not know what the patients had. And we doctors may get together to make records of what happens clinically with the patient, but the germ data are elsewhere. We need a common registry," he stressed.
"The main importance of a registry of this type is that it would allow a diagnostic and therapeutic decision to be made that is appropriate to the epidemiological profile of the country and the region, not looking at what they do in the North. Most likely, the best antifungal treatment for our country differs from what is indicated in the guidelines written elsewhere," said Afeltra.
Afeltra pointed out that in the United States, when an oncohematology patient does not respond to antimicrobial treatment, the first thing that doctors think is that the patient has aspergillosis or mucormycosis, in which the fungal infection is caused by filamentous fungi.
But an analysis of data from the REMINI registry ― the only prospective, observational, multicenter surveillance registry for invasive mycoses in immunocompromised patients (excluding HIV infection) in Argentina, which has been in existence since 2010 ― tells a different story. The most prevalent fungal infections turned out to be those caused by Aspergillus species, followed by Fusarium species. Together, they account for more than half of cases. Mucoral infections (mucormycosis) account for less than 6%. And the initial treatments for these diseases could be different.
Changes in the local epidemiology can occur because the behavior of phytopathogenic fungi found in the environment can be modified. For example, cases of chronic mucormycosis can be detected in China but are virtually nonexistent on this side of the Greenwich meridian, Afeltra said.
"Nature is not the same in geographical areas, and the fungi...we breathe are completely different, so patients have different infections and require different diagnostic and treatment approaches," he stressed.
Afeltra mentioned different fungi that are emerging locally and globally, including yeasts, septate, dimorphic, and pigmented hyaline fungi, that have a variable response to antifungal drugs and are associated with high mortality, "which has a lot to do with a later diagnosis," he said, noting that reports have increased worldwide. A barrier to sharing this information more widely with the professional community, in addition to the lack of records, is the difficulty in publishing cases or series of cases in indexed journals.
Another challenge in characterizing the phenomenon is in regard to taxonomic reclassifications of fungi. Such reclassifications can mean that "perhaps we are speaking of the same pathogen in similar situations, believing that we are referring to different pathogens," said Afeltra.
Clinical Pearls Related to Emerging Fungal Pathogens
Candida auris. This organism has emerged simultaneously on several continents. It has pathogenicity factors typical of the genus, such as biofilm formation and production of phospholipases and proteinases, although it has greater thermal tolerance. In hospitals, it colonizes for weeks and months. In Argentina, it is resistant to multiple antifungal agents. Sensitivity is variable in different geographical regions. Most strains are resistant to fluconazole, and there is variable resistance to the other triazoles (but which are not normally used to treat candidemia). In the United States, in vitro resistance to amphotericin B is up to 30%, and resistance to echinocandins is up to 5%. New drugs such as rezafungin and ibrexafungerp are being studied. Infection control is similar to that used to control Clostridium difficile.
Fusarium. This genus affects immunocompromised patients, including transplant recipients of solid organs and hematopoietic progenitor cells and patients with neutropenia. The genus has various species, included within complexes, such as F solani SC, F oxysporum SC, and F fujikuroi SC, with clinical manifestations similar to those of aspergillosis. In addition to the pulmonary and disseminated forms, there may be skin involvement due to dissemination from a respiratory focus or by contiguity from a focus of onychomycosis. In general, mortality is high, and responses to antifungal agents are variable. Some species are more sensitive to voriconazole or posaconazole, and others less so. All show in vitro resistance to itraconazole. In Argentina, voriconazole is usually used as initial treatment, and in special cases, liposomal amphotericin B or combinations. Fosfomanogepix is being evaluated for the future.
Azole-resistant aspergillosis. This infection has shown resistance to itraconazole and third-generation azole drugs. In immunocompromised patients, mortlaity is high. Early detection is key. It is sensitive to amphotericin B and echinocandins. It is generally treated with liposomal amphotericin B. Olorofima and fosfomanogepix are being studied.
Pulmonary aspergillosis associated with COVID-19. This infection is associated with high mortality among intubated patients. Signs and symptoms include fever, pleural effusion, hemoptysis, and chest pain, with infiltrates or cavitations on imaging. Determining the diagnosis is difficult. "We couldn't perform lung biopsies, and it was difficult for us to get patients out of intensive care units for CT scans. We treated the proven cases. We treated the probable cases, and those that had a very low certainty of disease were also treated. We came across this emergency and tried to do the best we could," said Afeltra. A digital readout lateral flow trial (Sōna Aspergillus Galactomannan LFA) for the quantification of galactomannan, a cell wall component of the Aspergillus genus, proved to be a useful tool for screening and diagnosing patients with probable pulmonary aspergillosis associated with COVID-19. the incidence of invasive mycosis was around 10% among 185 seriously ill COVID-19 patients, according to an Argentine multicenter prospective study in which Afeltra participated.
Scedosporium and Lomentospora. These genera are rarer septate hyaline fungi. Scedosporium is a complex of species. One species, S apiospermum, can colonize pediatric patients with cystic fibrosis. Lomentospora prolificans is a multiresistant fungus. It produces pulmonary compromise or disseminated infection. The response to antifungal agents is variable, with a high minimum inhibitory concentration for amphotericin B and isavuconazole. Patients are usually treated with voriconazole alone or in combination with terbinafine or micafungin. Olorofima is emerging as a promising treatment.
Afeltra has received fees from Biotoscana, Gador, Pfizer, Merck, and Sandoz.
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