Thursday, July 29, 2021
Drug-Resistant Fungi Threat Faces Cidara’s Phase III Antifungal Therapy
Multi-drug resistant fungi are rare but, as recent outbreaks show, are becoming less so. The FDA Watch List considers drug-resistant Candida auris (C. auris) an urgent threat, drug-resistant Candida species a serious threat, and azole-resistant Aspergillus Fumigatus worth watching – especially since person-to-person transmission of drug-resistant fungi has been recently documented.
The cure for this new threat may rest with Cidara Therapeutics’ new antifungal drug, rezafungin. It currently is completing two Phase III trials. One treats candidemia and invasive candidiasis. On the other, rezafungin is used as a prophylactic for the prevention of fungal infections in a high-risk hematology setting. It shows efficacy against Candida spp., Aspergillus spp., Pneumocystis spp. and dermatophytes, can be administered safely at high doses, and it can clear the body of infection quickly.
So far, it is outperforming caspofungin, the 20-year-old standard of care. “If approved, rezafungin will be the first new antifungal therapy to treat and prevent fungal infections in approximately 15 years,” Jeffrey Stein, Ph.D., president and CEO of Cidara Therapeutics, told BioSpace.
“Unlike other species of Candida, C. auris is more difficult to eradicate,” Stein said. “The problem is very similar to that of multi-drug-resistant bacteria. Treatment guidelines in the U.S. and Europe specify drugs from the echinocandin class as first-line treatment. Hospitals, however, have narrow cost margins so physicians are encouraged to try less expensive treatments first – typically azoles.” Unfortunately, those drugs may knock down the infection but fail to eradicate it, which allows those fungi to strengthen their resistance.
To hone the point, the Centers for Disease Control & Prevention (CDC) said about 85% of the C. auris isolates in the U.S. are resistant to azoles, 33% are resistant to amphotericin B, and 1% to echinocandins – the three major classes of antifungal medications.
Rezafungin is a member of the echinocandin class but, unlike other drugs in that class, can be administered at high doses for greater efficacy. Trials typically dosed patients with 400 mg initially, followed by 200 mg doses per week (400/200). “That’s why it works,” Stein said. “It also has a very long half-life, so it can be administered once per week.”
Data from Cidara’s completed STRIVE Phase II study showed that patients in the 400/200 mg rezafungin dosing group achieved a 100% negative blood culture six days after treatment. A more than 80% chance of a negative blood culture was achieved on day two. In contrast, patients receiving caspofungin intravenously each day only managed about a 70% chance of a negative blood culture by day three and maintained that with only a minimal further improvement by day eight, the end of the trial.
Consequently, patients treated with rezafungin were released from the ICU three days earlier than those receiving caspofungin. “We expect to have topline data from our ongoing Phase 3 ReSTORE study by the end of the year,” Stein said.
The difference this makes to patients can be significant. For example, Stein mentioned one patient with a chronic C. glabrata infection that was being treated with once-daily IV infusions of caspofungin. When the strain acquired an fks mutation, making it resistant to caspofungin, he was switched to amphotericin B and flucytosine, but developed renal failure. “He was in significant need of alternative options,” Stein said. “His physician contacted us for expanded access. He’s received weekly infusions of rezafungin for the past year, as an outpatient.”
In another example, Stein cited a case in which a patient had a bloodstream infection that infiltrated tissues. “This is very difficult to treat,” he pointed out. The patient had had a liver transplant that was complicated by intra-abdominal abscesses with C. krusei. “She was unable to clear the infection on micafungin…but after 12 doses of rezafungin, the infection had resolved.” Imaging at week 12 confirmed the resolution of the intra-abdominal abscesses.
“C. auris is an issue among the immunocompromised and those whose immune systems are debilitated,” Stein pointed out. About 100,000 million Americans fall into that category, he said, because it includes patients taking anti-inflammatory medications for arthritis or lupus, the elderly, and transplant, and cancer patients.
“Reports of echinocandin- or pan-resistant Candida auris (C. auris) cases in the U.S. are increasing,” according to the CDC. These strains often are resistant to multiple drugs. Two clusters of infections have emerged since January – one in Texas and the other in the District of Columbia, the CDC’s Meghan Lyman reported in the Mortality and Morbidity Weekly Report. “Each cluster involved common health care encounters and no known previous echinocandin exposure, suggesting transmission of pan- and echinocandin-resistant strains for the first time in the United States.”
Antifungal therapies have, historically, been neglected in terms of developing new anti-fungal options, and have been slow to come to market. San Diego-based Cidara is among a small group of companies active in this area.
Cidara will present updated clinical data from STRIVE and preclinical data regarding an in vitro evaluation of rezafungin activity against Candida and Aspergillus spp. isolates collected in Asia-Pacific countries at the International Society for Human and Animal Mycology (ISHAM) Asia Congress. The virtual congress takes place August 6-8, 2021.
Biogen to launch 5-year real world study of Aduhelm
While all eyes are on Biogen’s FDA-required Aduhelm trial that will determine whether the treatment actually aids Alzheimer’s patients, the company is involved in another real-world study in the works assessing its worth in an array of people coping with the memory-robbing disease.
That phase 4 observational study was first organized by Biogen ahead of Aduhelm’s nod in June, James Galvin, M.D., a professor of neurology at the University of Miami and the study’s presenting author, told Fierce Pharma. The study is intended to discover the drug's safety and impact on the disease in 6,000 patients treated with the antibody, according to details released during the Alzheimer’s Association International Conference on Thursday.
To be sure, it’s not the highly anticipated confirmatory trial the FDA required as part of Aduhelm’s accelerated approval. Rather, the observation trial outlined on Thursday—dubbed ICARE AD-US—will be seen as “complementary” to Biogen’s mandatory evaluations, Galvin noted.
The FDA gave Aduhelm the go ahead based on its ability to clear amyloid plaque in a patient’s brain—a hallmark of Alzheimer’s disease. As part of the agency's approval conditions, Biogen will have to show that the amyloid clearance also leads to a slowing down of cognitive decline.
In comparison, ICARE’s goal will be to determine how Aduhelm, also known as aducanumab, performs in the real world, rather than in controlled clinical trials.
“I think something like this is incredibly important to do,” Galvin, who also served as an investigator for Biogen’s late-stage Aduhelm trials, told Fierce Pharma.
All the sites are ready to begin dosing patients, but enrollment isn’t expected to pick up until Medicare and other third-party payers decide which patients will be reimbursed for the $56,000-per-year treatment.
“I don’t think this study will get up and rolling until we understand that,” Galvin said.
The primary objective of the study will be to evaluate how well Aduhelm slows the progress of Alzheimer's in dosed patients, measured by a patient’s cognition, function and behavior as well as their performance through various assessment tools.
Researchers will also look at how Aduhelm impacts healthcare resources, quality of life and overall disease burden. The study will enroll patients in line with the FDA’s narrowed label, aiming to do so over four years at roughly 200 clinical sites across the U.S. Researchers will collect data over five years, although the timeline could be extended, Galvin said.
One gray area researchers intend to investigate is Aduhelm’s impact on diverse patients, including at least 500 African American and 500 Hispanic people. Biogen has faced pushback over the lack of patient diversity in its controversial phase 3 studies, known as Emerge and Engage.
ICARE will also include people who may not typically qualify for clinical trials, like those with diabetes, high blood pressure and cancer.
As part of the observational study, researchers will also collect blood plasma and serum from patients so Biogen can measure changes and, potentially, improvement via blood samples, Galvin said. Currently, the only way of doing that is through PET scans or lumbar punctures that could cost patients thousands.
“I think there’s a lot of amazing information that could be gleaned from this, but you have to know what it can’t do,” Galvin said. “And what it can’t do is be used as a confirmation study for the FDA because there’s no control group. There’s no placebo.”
AstraZeneca sees China growth slowing
Over the past few years, China has been offering AstraZeneca bragging rights. But the company’s business in the country is coming to a turning point after being exposed to the government’s price-cutting scheme and local competition—and investors have caught wind.
During a conference call Thursday, Wall Street analysts piled into AstraZeneca’s China performance, pressing management on whether the company can sustain its double-digit sales growth in the country.
The short answer? Expect slower growth going forward.
“Slower growth in China is no question,” AstraZeneca CEO Pascal Soriot told investors on the call. “We believe we can continue growing [and] maintain our position of leadership, but it’s going to be more difficult moving forward.”
AstraZeneca's Chinese business pulled in sales of $1.53 billion in the second quarter after a 12% year-over-year growth at constant currencies. But problems are showing.
As one analyst noted during the call, more than $1 billion in annual sales from older AZ products are now exposed to China’s volume-based procurement (VBP) initiative, a price-cutting program that targets off-patent drugs.
Cholesterol drug Crestor, blood thinner Brilinta and acid reflux med Nexium have all suffered as a result. Brilinta, for example, saw emerging markets sales drop 40% at constant currencies to $180 million in the first six months of 2021.
Over the past two to three years, VBP has become “quite a challenge,” AZ’s international and China market chief Leon Wang said on the call. In response, the company has resorted to multichannel marketing, turning to the retail pharmacy market to soften the blow of tender losses.
In addition, AZ has been working to ink local commercialization deals to maintain its presence in China, Wang said.
AZ’s competition isn’t just coming from generics, though. China has a growing biopharma industry where many companies are piling into a few validated drug targets, threatening incumbent foreign drugmakers.
Case in point: Hansoh Pharma is seeking approvals for its third-generation EGFR inhibitor Ameile (almonertinib) for newly diagnosed EGFR-mutated non-small cell lung cancer. It comes as AZ’s flagship EGFR inhibitor Tagrisso has just been included for national reimbursement in China in the front-line setting.
Competition is indeed “severe” from local firms, Wang said, but the company is working to add new drugs and indications to the market and is noticing increased volumes from national reimbursement deals.
“With our commercial capability, we will definitely make sure that we can stabilize and continue growing,” Wang said.
Another area AZ sees as a growth opportunity in China is rare diseases. In announcing its recent $39 billion acquisition of Alexion late last year, Soriot highlighted the potential to expand the Boston firm’s rare disease portfolio to China.
Problem is, China is currently focused on reining in healthcare expenditures and might not respond favorably to pricey rare disease meds.
AZ’s chief financial officer and incoming Alexion head Marc Dunoyer acknowledged that the reimbursement infrastructure for rare disease drugs in China isn’t as advanced as it is in many developed economies. The rare disease market in China is still small, but there’s a growing recognition of its importance from authorities, he added.
“We were all surprised by the speed at which the oncology market grew in China,” Dunoyer said on the call. “Even if we don’t expect rare disease to grow at the same speed, it is likely that the speed at which the rare disease grows in China is going to be faster than other markets of the world.”
Wang noted that Alexion could first introduce Alexion’s portfolio to China’s Guangdong-Hong Kong-Macau Greater Bay Area. A special program currently allows cross-border use of drugs and medical devices in the province of Guangdong—a wealthy territory with a large population—as long as the product is approved in Hong Kong. That offers an easy regulatory pathway for drugs already approved in the U.S. and the EU.
Ultimately, AZ hopes to shape the market by working with Chinese authorities to develop guidance on how rare disease drugs can be included for national coverage at reasonable prices, Wang said.
Overall, Wang confirmed that AZ can still grow its China business at low double digits in the second half of the year, but the company declined to offer an outlook for 2022.
COVID app told nearly 690,000 to isolate in England, Wales
Almost 690,000 people in England and Wales were contacted by the official COVID-19 health app and advised to isolate after coming into contact with someone with the virus in the week to July 21, official data shows.
Businesses in all sectors have complained that they are struggling to maintain operations when so many staff have been told to stay at home to break the transmission. The government has said that some essential workers can now use daily testing to avoid having to isolate.
https://news.yahoo.com/covid-app-told-nearly-690-100225940.html