AstraZeneca’s star China biz slows on Tagrisso price; Alexion may rescue

 China has delivered enviable growth for AstraZeneca in the past. But in the third quarter, the country became the main drag on AZ’s performance, thanks to a price cut to the company’s top-selling drug.

AstraZeneca’s China business only increased sales by 2% in constant currencies for Q3, in stark contrast to the double-digit growth it has routinely posted in recent years.

EGFR lung cancer med Tagrisso struggled in China with sales down 10% in the first nine months, curtailing its worldwide sales growth to 13%—to $3.7 billion—for that period. Because of China, Tagrisso even suffered a 4% sequential sales decline in the third quarter. 

AstraZeneca CEO Pascal Soriot said the company still believes China could turn in high single-digit growth in the next four to five years. “It is clear that China is slowing down, but it remains a very important market for us,” Soriot said during a conference call Friday.

To hear Soriot tell it, the sales volume for key medicines is expanding in China, but it’s not fully compensating for lower prices, at least for now.

For Tagrisso especially, the drug’s indication for newly diagnosed lung cancer was added to national reimbursement in March. After that, Tagrisso enjoyed an inventory build-up and a “bolus” of sales, thanks to first-line switches from earlier-generation therapies, Dave Fredrickson, AZ’s oncology business chief, told investors on the call. Those factors helped in the second quarter but weren’t at play in the third quarter.

Still, AZ expects growing Tagrisso sales volume in China to compensate for the price reduction it took to gain national coverage, Fredrickson said.

As AZ has a history of moving more quickly than its peers in introducing novel medicines to China, the company is now looking to new products for the country. These could come from AZ’s newly bought Alexion.

Alexion, which is now AZ’s rare disease unit, has already established a dedicated team in China and is in talks with local drug regulators to gain market access, Alexion CEO Marc Dunoyer said on the call. The company hopes to have its first approval in 2022 and a possible launch in 2023, he added.

After AZ wrapped up the Alexion acquisition in mid-July, rare blood disorder therapies Soliris and Ultomiris brought in sales of $1.1 billion for the rest of the third quarter. Alexion has converted more than 70% of paroxysmal nocturnal hemoglobinuria patients from Soliris to the newer Ultomiris, whose $297 million haul during the period marked a 31% increase year over year.

But as Wolfe Research analyst Tim Anderson pointed out during the call, competitors are on the horizon. Most notably, Novartis’ oral iptacopan is in development for PNH and other territories now held by the Alexion antibodies, with first FDA filings expected in 2023.

Beyond its existing business units of oncology, biopharmaceuticals and rare disease, AZ is creating a new department to manage its COVID-19-related products, including its COVID vaccine Vaxzevria and antibody product AZD7442.

Vaxzevria’s haul in the third quarter reached $1.05 billion, bringing the nine-month total to $2.22 billion. As for AZD7442, the company expects an FDA emergency use authorization decision this year for what would be the first long-acting COVID antibody prevention therapy.

https://www.fiercepharma.com/pharma/astrazeneca-s-star-china-business-slows-down-tagrisso-a-main-drag-but-possible-help-its-way

Late to the party: Europe near approving Roche, Celltrion antibodies for COVID

 Nearly a full year after the U.S. gave Regeneron’s antibody cocktail for COVID-19 patients emergency authorization, Europe is on the verge of approving the monoclonal antibody duo. The European Medicines Agency's committee for human medicines also has recommended another antibody treatment for approval, Celltrion’s regdanvimab.

The EMA's Committee for Medicinal Products for Human Use has passed the recommendations to the European Commission for approval. The Regeneron cocktail of casirivimab and imdevimab, which is marketed outside of the U.S. by Roche and known commercially as Ronapreve, is recommended for COVID-19 patients who do not require supplemental oxygen and are at risk to progress to a severe form of the disease. It also is recommended for use as post-exposure prophylaxis. While the recommendations cover all adults, they also include adolescents 12 years or older weighing at least 40 kilograms, or roughly 88 pounds.

The recommendation for Celltrion’s regdanvimab, known commercially as Regkirona, covers the same subset of COVID-19 patients as Ronapreve's advice but only for adults and not in the preventive setting. Regkirona was approved for use in Celltrion’s home country, South Korea, in September.

The only other treatment approved for COVID-19 patients in Europe is Gilead’s Veklury, which is an antiviral treatment. It's Europe approval in June 2020 was for the same age groups but for a different population compared to Ronapreve and Regkirona—those already hospitalized with pneumonia and requiring supplemental oxygen. Veklury is also under review in Europe to extend its use to adults who do not require supplemental oxygen. 

In June, the European Union acquired 55,000 courses of Ronapreve. Two months later, it received conditional marketing authorization in the U.K.

The EMA recommendation for Ronapreve was based on a study of 2,385 patients. It showed that 0.9% of those treated with Ronapreve were hospitalized or died within 29 days compared to 3.4% who were given a placebo.

Additionally, in a study of more than 200 people, of those treated with Ronapreve to prevent infection after a household member contracted the virus, 29% tested positive for COVID-19 as opposed to 42% of those received a placebo.

The recommendation for Regkirona was based on a study of 880 patients. While 3.1% of those treated with Regkirona were hospitalized, required oxygen or died, 11.1% provided placebo had those outcomes.

The positive recommendations come more than four months after the European Union identified four monoclonal antibody treatments to prioritize for examination. One was GlaxoSmithKline and Vir Biotechnology’s sotrovimab, which was given emergency authorization in the U.S. in May of this year.

The other was Eli Lilly’s combination of bamlaniviimab and etesevimab, which was initially given the go-ahead in the U.S. last year before losing its emergency authorization in June and then regaining it two months later. Last week, Lilly withdrew its application for approval of its antibodies in Europe because of a lack of demand.

https://www.fiercepharma.com/pharma/late-to-party-europe-finally-verge-approving-antibodies-for-covid-19

Astra presses on with bispecifics

 With bispecific antibodies again set to be a major focus of the Ash conference Astrazeneca has moved to remind investors that it has a major presence with this approach. The group’s third-quarter earnings today included news that bispecifics against Tigit and Tim3 had entered the clinic, as well as a reminder about MEDI5752, an anti-PD-1/CTLA-4.

MEDI5752 was known to have been Astra’s attempt to improve on the simple anti-CTLA-4 MAb tremelimumab, so its advancement is ironic given that treme might be turning a corner. And the group’s Tigit and Tim3 approaches will be seen as a challenge to Roche, Novartis and Glaxosmithkline, though of course Astra is very much playing catch-up.

The Tim3 space is chiefly a battle between Novartis’s sabatolimab and Glaxosmithkline/Anaptysbio’s cobolimab. The latter, a project Glaxo acquired along with Tesaro, is an important pillar of this UK group’s tenuous attempt to regain a presence in oncology, and is in phase 2/3 trials for several solid tumour indications.

Novartis, meanwhile, is limiting sabatolimab to haematological cancers, with late-stage trials in myelodysplastic syndromes and AML. Astra’s highlighted bispecific, AZD7789, which hits PD-1 and Tim3, started its first-in-human study in solid cancers in September, according to clinicaltrials.gov.

Another interesting big pharma player in Tim3 is Lilly, which also had a PD-1/Tim3 bispecific, LY3415244, derived from a tie-up with Zymeworks. This has since been terminated, though a straight anti-Tim3 MAb, LY3321367, is in two phase 1 combo trials, and has shown some promise in small-cell lung cancer.

Hot Tigit

Tigit, meanwhile, is a much hotter space than Tim3, with Roche heading the pack courtesy of its huge programme for tiragolumab, and biotech players including Compugen, Arcus, Mereo and Iteos, the last of which Glaxo linked up with for $625m up front in June.

Astra today said its candidate, AZD2936, an anti-PD-1/Tigit bispecific, was new into phase 1. Clinicaltrials.gov lists its Artemide-1 study as testing monotherapy in PD-L1-expressing NSCLC. This approach makes sense as tiragolumab has so far shown activity in combination with Tecentriq, and the bispecific approach combines both modalities in one molecule, at least in theory.

Tigit watchers are also keeping an eye on Arcus, whose domvanalimab could see Gilead opt in to development, and which cryptically revealed this week that the opt-in “review process” had been “initiated”. Notably, however, investors have yet to see any meaningful domvanalimab data.

And biotech followers will note that Compugen yesterday revealed the expansion of its tie-up with Bristol, with the big pharma group paying $20m for a premium-priced equity stake. Compugen has an Fc-silent anti-Tigit MAb, COM902, as well as COM701, which targets PVRIG, a protein in the same mechanistic axis. Clinical data on a triple combo of Opdivo, COM701 and Bristol’s own anti-Tigit, BMS-986207, presented at SITC today, show nothing better than stable disease, however.

Treme replacement?

The final part of Astra’s bispecific pitch today concerns the PD-1/CTLA-4-targeting MEDI5752, whose advancement into the clinic Evaluate Vantage had noted over a year ago.

That was when Astra was in dire need of a plan B, as tremelimumab had failed every late-stage trial it had been in. But this year treme succeeded first in Poseidon, and then in the Himalaya study, making it a serious contender for approval as part of an Imfinzi combo, the latter success coming courtesy of a novel dosing regimen called Stride.

MEDI5752 is now in three phase 1 trials, though first data are not expected until beyond 2022.

Other pipeline changes revealed by Astra today include an inhaled Jak1 for asthma, AZD4604, moving into a phase 1 volunteer study, following in the footsteps of another inhaled Jak, AZD0449. This will be relevant for Theravance and Kinaset.

The separate discontinuation of MEDI5395, a GM-CSF-expressing oncolytic virus, should come as little surprise given the appalling track record of these projects.

https://www.evaluate.com/vantage/articles/news/trial-results/astra-presses-bispecifics

J&J splits off consumer – but not medtech

 Johnson & Johnson has plumped to follow Glaxo’s model, rather than the path pioneered by Abbvie. J&J plans to spin off its consumer arm, the largest of its kind among pharma companies, according to Evaluate Pharma, in 2023, probably via a stock market listing. Glaxo, thanks to a controlling stake in a joint venture with Pfizer and products it acquired from Novartis, currently has the second-largest consumer business, though not, of course, for long. The as-yet unnamed group that will be spun out of J&J will become the home of brands such as Neutrogena and Listerine, but perhaps more importantly of J&J’s talcum powder products, the subject of thousands of lawsuits claiming that they cause cancer. Another intriguing facet of the split-up is that J&J has opted to keep its pharma products and medical devices together, saying these serve similar patients and healthcare providers and operate in similar regulatory and competitive environments. But splitting them apart has worked well for Abbvie and Abbott Laboratories, and General Electric announced just this week that it would spin its medtech operations into a separate company within the next two years. Perhaps J&J might have yet more streamlining to do.

https://www.evaluate.com/vantage/articles/news/snippets/jj-splits-consumer-not-medtech

Fewer Hepatitis C Patients Seeking Treatment

 The number of people with hepatitis C virus (HCV) treated with direct-acting antiviral agents (DAAs) dropped sharply in 2020, accelerating a decline that began in 2015, CDC researchers found.

While 843,362 individuals from 2014-2020 were estimated to receive DAAs for HCV, only 83,740 initiated DAA treatment in 2020, down from 114,893 in 2019 and a high of 164,247 in 2015, reported Eyasu Teshale, MD, of the CDC, and colleagues.

On average, 120,000 patients with HCV were given DAA treatment annually from 2014 to 2020, which is significantly fewer than the goal set by the National Academies of Science, Engineering, and Medicine that requires at least 260,000 HCV patients to be treated annually in order to achieve HCV elimination by 2030.

These data were released ahead of their planned presentation at the American Association for the Study of Liver Diseases (AASLD) virtual annual meeting.

"We know COVID-19-related disruptions to hepatitis C testing and treatment likely contributed to the low treatment numbers in 2020, but seeing this number next to the previous annual trends underscores the magnitude of the pandemic's impact on treating hepatitis C in the United States," Teshale told MedPage Today. "While the study doesn't tell us why treatment peaked in 2015, it's likely related to many people with hepatitis C waiting to be treated with DAAs as soon as they became available beginning in 2013."

"This research is critical as it allows us to track progress towards HCV elimination goals," said Risha Renee Irvin, MD, MPH, of Johns Hopkins University School of Medicine in Baltimore, who was not involved in this study. "Direct-acting antiviral agents have undoubtedly expanded access to treatment but this data highlights the additional work that must be done to reach HCV elimination metrics."

Daniel Raymond, BA, of the National Viral Hepatitis Roundtable (NVHR) in Washington D.C., called these data "confusing and disappointing" in a statement.

"In spite of dramatic declines in the cost of these medications, at the current rate of treatment, we are estimated to fall significantly short of our goal to eliminate viral hepatitis by 2030," he said.

Teshale and colleagues evaluated IMS Health & Quintiles (IQVIA) data from 2014 to 2020 on 843,362 individuals with HCV who had evidence of receiving DAAs. They were stratified based on insurance status, age group, sex, race, type of DAA, and treatment year.

Overall, 60% of the individuals were men, and almost two-thirds were "baby boomers." The authors noted that race/ethnicity data was missing for two-thirds of the cohort, but of those with data available, 68% of individuals were white. Sixty percent of prescribers were specialists. The two most commonly prescribed DAA regimens were sofosbuvir/velpatasvir (Epclusa) in 46% and glecaprevir/pibrentasvir (Mavyret) in 44%.

Interestingly, the annual proportion of DAAs dispensed to baby boomers declined sharply from 2014 to 2020 (74% vs 46.3%, respectively), with a corresponding increase among those born after 1965 (17% vs 51%).

Likewise, the proportion of Medicare-paid claims declined from 30% to 25% during the study period, but the proportion of Medicaid-paid claims increased from 7% to 15%.

Raymond called for confronting "the root causes of barriers to treatment" for the most vulnerable populations, including "removing policy restrictions that prevent people from accessing hepatitis C treatments in state Medicaid programs, implementing and financing proven care coordination and patient navigation models, and reaching the most vulnerable populations with testing and linkage to care," he added.

"Additionally, I agree that the removal of any restrictions on receipt of HCV treatment based on provider status, liver fibrosis, and substance use history should be prioritized," said Irvin.

The analysis had several limitations, researchers acknowledged, including the absence of demographic information for a large proportion of the cohort. Data also only came from one source, a longitudinal prescription claims database, which excludes data from the Veteran's Affairs health system and long-term care pharmacies.

Disclosures

CDC researchers declared no conflicts of interest. The AASLD meeting is supported by Pfizer.

Primary Source

American Association for the Study of Liver Diseases

Source Reference: Teshale E, et al "Hepatitis C treatment in the United States, 2014-2020" AASLD 2021; Abstract #926.

https://www.medpagetoday.com/meetingcoverage/aasld/95605

Dementia Linked to Inflammatory Foods

 Diets with higher inflammatory potential were tied to an increased risk of incident dementia, a prospective observational study showed.

Each unit increase in dietary inflammatory index scores was associated with a 21% higher risk of dementia over 3 years (HR 1.21, 95% CI 1.03-1.42, P=0.023), reported Nikolaos Scarmeas, MD, PhD, of Columbia University in New York City and the National and Kapodistrian University of Athens Medical School in Greece, and co-authors.

Compared with participants with the lowest inflammatory diet scores, those with the highest scores were three times more likely to develop incident dementia (HR 3.01, 95% CI 1.24-7.26, P=0.014), the researchers wrote in Neurology.

"A diet with a more anti-inflammatory content seems to be related to lower risk for developing dementia within the following 3 years," Scarmeas told MedPage Today. Available dementia treatments are not very effective, he said -- "it's quite important that we find some measures to partially prevent it."

"Diet might play a role in combating inflammation, one of the biological pathways contributing to risk for dementia and cognitive impairment later in life," he added.

Evidence suggests certain foods, nutrients, and non-nutrient food components can modulate inflammatory status acutely and chronically. Earlier prospective research looked at dietary inflammatory potential and cognitive decline only in women, not in both sexes, the researchers noted.

Scarmeas and co-authors analyzed data from 1,059 older adults in the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD), a population-based study that investigates associations between nutrition and age-related cognition in Greece. People with dementia at baseline were excluded from the analysis.

Participants had a mean baseline age of 73.1 and a mean 8.2 years of education; 40.3% were men. Dietary intake was evaluated through a semi-quantitative food frequency questionnaire validated for the Greek population and administered by a trained dietitian.

Foods and nutrients associated with the inflammatory biomarkers interleukin (IL)-1β, IL-4, IL-6, L-10, tumor necrosis factor (TNF)-α, and C-reactive protein in other studies were assigned a value and tallied to obtain a diet inflammatory index score. Higher dietary inflammatory index scores indicated a more inflammatory diet.

People in the first tertile had the lowest scores (-5.83 to -1.76, indicating a more anti-inflammatory diet), which represented about 20 servings of fruit, 19 of vegetables, four of legumes, and 11 of coffee or tea a week, on average. People in the third tertile had the highest scores (0.21 to 6.01) and a more pro-inflammatory diet, with a weekly average of nine servings of fruit, 10 of vegetables, two of legumes, and nine of coffee or tea.

Over an average follow-up of 3.05 years, 62 people were diagnosed with dementia. Higher dietary inflammatory index scores correlated with higher dementia risk. A gradual risk increase across higher tertiles suggested a dose-response relationship between the inflammatory potential of diet and incident dementia, Scarmeas and co-authors observed.

The relatively short follow-up period in this study raised the possibility of reverse causality, but further analysis showed the findings were not moderated by the presence of mild cognitive impairment at baseline.

Food frequency questionnaires may be subject to measurement error, the researchers acknowledged. Data about some dietary components, including eugenol, ginger, onion, turmeric, garlic, oregano, pepper, rosemary, and saffron, were not available. In addition, serum levels of inflammatory biomarkers were not obtained.

"Our results are getting us closer to characterizing and measuring the inflammatory potential of people's diets," Scarmeas said. "That, in turn, could help inform more tailored and precise dietary recommendations and other strategies to maintain cognitive health."

Disclosures

The study was supported by the Alzheimer's Association, the European Social Fund, and the Greek Ministry of Health and Social Solidarity.

Scarmeas reported personal fees from Merck Consumer Health, Eisai, and NIH. Co-authors had no disclosures.

Primary Source

Neurology

Source Reference: Charisis S, et al "Diet inflammatory index and dementia incidence: a population-based study" Neurology 2021; DOI: 10.1212/WNL.0000000000012973.

https://www.medpagetoday.com/neurology/dementia/95626

After Long Wait, Biden Taps Robert Califf to Again Lead FDA

 The White House tapped cardiologist Robert Califf, MD, to once again head the FDA.

In a statement formally announcing his decision, President Biden praised Califf's clinical research expertise and leadership skills, and said he is the right person to lead the agency and the country out of the COVID-19 pandemic.

"As the FDA considers many consequential decisions around vaccine approvals and more, it is mission critical that we have a steady, independent hand to guide the FDA," he said.

Califf will ensure that "science and data drive decision-making" at the agency, Biden added. He also recalled the "strong bipartisan support" that the cardiologist received from the Senate in 2016, when Califf first served as FDA Commissioner under the Obama administration, and urged lawmakers to swiftly confirm him.

Califf is a professor at the Duke University School of Medicine in Durham, North Carolina, and previously served as vice chancellor of the school. He also founded the Duke Clinical Research Institute, and oversees clinical policy at Verily Life Sciences.

From 2016 to 2017, Califf served as commissioner after being confirmed by the Senate in a vote of 89-4.

HHS Secretary Xavier Becerra congratulated Califf in a press release, stating that he "knows the job and is ready for the challenge."

Becerra also acknowledged Janet Woodcock, MD, who has been serving as the acting commissioner, for her "instrumental" contributions to the agency during a difficult period. "We will continue to be on solid footing because of her continued leadership and focus on strengthening FDA and supporting its workforce," he said.

'A Poor Choice'

Not everyone was pleased with the news. Some Democratic lawmakers, including Joe Manchin (D-W.Va.), were quick to make their disappointment with Califf's nomination known.

"Dr. Califf's nomination makes no sense as the opioid epidemic continues to wreak havoc on families across this country with no end in sight," said Manchin in a statement he shared on Twitter.

"I have made it abundantly clear that correcting the culture at the FDA is critical to changing the tide of the opioid epidemic. Instead, Dr. Califf's nomination and his significant ties to the pharmaceutical industry take us backwards not forward. ... I could not support Dr. Califf's nomination in 2016 and I cannot support it now," he continued.

In October, Sen. Richard Blumenthal (D-Conn.) said that if Califf were to be nominated, "I expect I would oppose him," according to Bloomberg Government.

Sen. Maggie Hassan (D-N.H.) also expressed reservations over Califf's ties to the pharmaceutical industry. Given the continuing substance misuse epidemic, Hassan called for "an FDA Commissioner that acts independently from the pharmaceutical industry, makes decisions based on the science, and puts the health and safety of Americans first."

"I have been deeply troubled by some of the FDA's past decisions -- especially as it relates to the approving and labeling of opioid-based medications -- and the FDA has yet to make clear what it is doing to learn from its actions," she noted in a statement.

Hassan added that she would "thoroughly review" Califf's record, but stopped short of saying she would vote against him.

Public Citizen, a consumer advocacy group, immediately panned Biden's choice, arguing that Califf would put the pharmaceutical industry's interests ahead of the public's.

In a statement, Michael Carome, MD, director of Public Citizen's Health Research Group, recalled the consulting fees Califf received from more than 19 pharmaceutical companies before serving as FDA commissioner the first time, as well as "the tens of thousands of dollars" he received from drug and device companies afterwards.

"Califf was a poor choice for FDA commissioner when he was nominated by Obama in 2015 and he remains a poor choice today," he added.

'A Proven Leader'

Others, however, appeared happy about the nomination.

Sen. Patty Murray (D-Wash.) stressed the need for a Senate-confirmed leader to oversee and support scientists during an "historic pandemic" in a press statement.

"Dr. Califf has led the Agency before, and was confirmed last time around in a strong, bipartisan vote. I look forward to working with him to see our nation through this pandemic and to tackle other critical challenges like the ongoing opioid crisis, rising youth tobacco use, high drug prices, health inequities, and more," she said.

Califf's nomination also spurred accolades from research advocates, including Ellen Sigal, PhD, chair and founder of Friends of Cancer Research. "Dr. Califf's commitment to science, dedication to research, and fierce advocacy for patients unequivocally makes him the right leader at this critical time," she said in a statement. "There are few individuals better positioned to continue to build confidence in the agency, ensure science-based regulatory standards, and build a strong foundation for the future."

Among those rumored to have been considered for the role of FDA commissioner was Michelle McMurry-Heath, MD, PhD, CEO of Biotechnology Innovation Organization, as well as Woodcock, whose term as acting commissioner is slated to end November 15. However, White House officials, speaking anonymously, confirmed in August that it was unlikely that Woodcock would be given the opportunity.

https://www.medpagetoday.com/publichealthpolicy/fdageneral/95632