Israel study: Pfizer Paxlovid may not be effective in treating adults under 65

 One of the dangers of investing in Pfizer (PFE 1.61%) today is that its business depends heavily on its COVID-19 pill and vaccine for revenue growth. This year, for instance, sales from its COVID-19 products will account for about half of its top line. That's a key reason why investors aren't paying much of a premium for the stock; there's a fair bit of uncertainty about how its financials will look in a year or two.

Making that haziness even worse is a recently published study that calls into question the effectiveness of Pfizer's COVID-19 treatment pill, Paxlovid. Let's take a look at all these factors and what to make of them.

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Is Paxlovid ineffective for non-seniors?

The Israeli study was published in The New England Journal of Medicine. It examined about 109,000 COVID-19 patients during the ongoing omicron wave of the virus, and found that while Paxlovid was beneficial for those who were 65 and older, it wasn't as helpful for younger patients. Based on the data for those between 40 and 65, the study concluded that "no evidence of benefit was found in younger adults."

The study wasn't randomized, nor was there a control group, so it's by no means definitive. However, it could lead to more research on Paxlovid to see if the pill is a useful option for younger people. In December,  the Food and Drug Administration issued an Emergency Use Authorization for Paxlovid as a treatment for mild to moderate cases of COVID-19 in adults and children as young as 12. Those with the virus are advised to start taking the pill within five days of developing symptoms.

A big year from its COVID-19 products

In 2022, Pfizer projects that its COVID-19 vaccine and pill will generate $54 billion in revenue for the company. Of that tally, Paxlovid is expected to account for $22 billion. In total, Pfizer is projecting around $100 billion in revenue from all of its products this year. To put that into perspective, consider that in 2020, Pfizer's revenue totaled $41.9 billion. Paxlovid's 2022 sales will equal more than half that amount.

It's likely that the healthcare company's sales will decline next year as people's concerns about COVID-19 continue to ease. But if countries and medical regulators grow concerned that Paxlovid is only effective in treating seniors, that could result in a more significant revenue decline. Some countries are already hesitant about Paxlovid because it can have harmful interactions with other drugs.

Merck has its own COVID-19 treatment  on the market: Molnupiravir. That pill isn't as effective at keeping patients out of the hospital as Paxlovid, but in some markets, it's preferred because it has fewer potentially risky interactions with other drugs. Molnupiravir could potentially pull some market share away from Paxlovid, especially in light of this new study.

https://www.fool.com/investing/2022/09/09/this-troubling-news-could-put-a-dent-in-pfizers-sa/

Risk factors for heart disease and stroke largely similar in men and women globally

 Women and men share most of the same risk factors for cardiovascular disease (CVD), a large international study has found -- the first such study to include people not only from high income countries, but also from low- and middle-income countries where the burden of CVD is the greatest.

The study was published today in The Lancet.

The global study assessed risk factors, including metabolic (such as high blood pressure, obesity and diabetes), behavioural (smoking and diet), and psychosocial (economic status and depression) in about 156,000 people without a history of CVD between the ages of 35 and 70. Living in 21 low, middle and high-income countries on five continents, they were followed for an average of 10 years.

"Women and men have similar CVD risk factors, which emphasizes the importance of a similar strategy for the prevention of CVD in men and women," said the paper's first author Marjan Walli-Attaei, a research fellow at the Population Health Research Institute (PHRI) of McMaster University and Hamilton Health Sciences (HHS).

Overall, women had a lower risk of developing CVD than men, especially at younger ages.

However, diet was more strongly associated with CVD risk in woman than men -- "something that's not been previous described, and which requires independent confirmation," said Salim Yusuf, lead investigator of the study, senior author, executive director of PHRI, professor of medicine at McMaster University, and cardiologist at HHS.

High levels of bad (LDL) cholesterol and symptoms of depression were more strongly associated with CVD risk in men than in women. The patterns of these findings were generally similar in high-income countries and upper-middle-income countries, and in low-income and lower-middle-income countries.

Funding was provided by the PHRI, Hamilton Health Sciences Research Institute, the Canadian Institutes of Health Research (including through the Strategy for Patient-Oriented Research via the Ontario SPOR Support Unit), the Ontario branch of the Heart and Stroke Foundation, and the Ontario Ministry of Health and Long-Term Care.

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Story Source:

Materials provided by McMaster University. Original written by Heather Angus-Lee. Note: Content may be edited for style and length.

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Journal Reference:

1. Marjan Walli-Attaei, Annika Rosengren, Sumathy Rangarajan, Yolandi Breet, Suraya Abdul-Razak, Wadeia Al Sharief, Khalid F Alhabib, Alvaro Avezum, Jephat Chifamba, Rafael Diaz, Rajeev Gupta, Bo Hu, Romaina Iqbal, Rosnah Ismail, Roya Kelishadi, Rasha Khatib, Xinyue Lang, Sidong Li, Patricio Lopez-Jaramillo, Viswanathan Mohan, Aytekin Oguz, Lia M Palileo-Villanueva, Katarzyna Poltyn-Zaradna, Sreelakshmi P R, Lakshmi V M Pinnaka, Pamela Serón, Koon Teo, Sejil T Verghese, Andreas Wielgosz, Karen Yeates, Rita Yusuf, Sonia S Anand, Salim Yusuf. Metabolic, behavioural, and psychosocial risk factors and cardiovascular disease in women compared with men in 21 high-income, middle-income, and low-income countries: an analysis of the PURE study. The Lancet, 2022; 400 (10355): 811 DOI: 10.1016/S0140-6736(22)01441-6

https://www.sciencedaily.com/releases/2022/09/220909094545.htm

CDC: More Kids Hospitalized With Respiratory Disease Linked to Non-Polio Enterovirus

 Healthcare providers reported an increase in pediatric hospitalizations across the country for severe respiratory illnesses last month, which may be linked to an enterovirus strain that causes rare neurologic complications, the CDC announced in a Health Alert Network advisory on Friday.

In August, clinicians and health systems in several regions of the U.S. reported an increase in children hospitalized for severe respiratory illnesses who also tested positive for rhinovirus (RV) or enterovirus (EV), the advisory stated. Upon further testing, more of those cases tested positive for enterovirus D68 (EV-D68), a non-polio enterovirus linked to uncommon neurologic complications.

Between April and August 2022, the CDC noted a substantial increase in EV-D68 cases among children who were tested at facilities within the New Vaccine Surveillance Network (NVSN), which has seven sites across the country. The number of EV-D68 cases identified at all sites between July and August this year was greater than those detected in 2021, 2020 and 2019, the agency said.

In most cases, EV-D68 causes acute respiratory illness in children, with common symptoms in hospitalized patients including cough, shortness of breath, and wheezing. Fever has also been reported in approximately half of known cases.

EV-D68 also has been associated with acute flaccid myelitis (AFM), a rare neurologic disorder that can result in muscle pain and limb weakness.

As of Aug. 30, the CDC has not received any reports of AFM cases. "However, increases in EV-D68 respiratory illnesses have typically preceded cases of AFM, indicating that increased vigilance for AFM in the coming weeks will be essential," the agency stated.

The CDC recommended that healthcare providers consider EV-D68 as a possible cause of acute, severe respiratory illness in children, and make testing for EV or RV a typical part of their diagnostic routine.

The agency noted that rhinovirus and enterovirus have a very similar clinical presentation, and are almost indistinguishable from one another on the multiplex assays that are typically used in clinical settings. Distinguishing between rhinoviruses or enteroviruses, or identifying a specific type of either virus, requires typing using molecular sequencing or an EV-D68-specific real-time reverse transcription-polymerase chain reaction (rRT-PCR) test.

The agency also urged clinicians to "strongly consider AFM in patients with acute flaccid limb weakness, especially after respiratory illness or fever, and between the months of August and November 2022."

Additionally, as there are no available vaccines or antiviral therapies for any rhinovirus or enterovirus, the CDC recommended that clinicians provide supportive clinical management for RV or EV, including EV-D68.

Previous outbreaks of EV-D68 occurred in 2014, 2016, 2018, and to a lesser degree in 2020. These outbreaks were followed by increased AFM cases in the fall of 2014, 2016 and 2018, the CDC stated.

During the most recent outbreak of EV-D68 cases in 2018, the median age of children who sought inpatient or emergency department care for their illness was 3 years old, but children and adolescents of any age can be affected, the CDC said. While EV-D68 is not well understood in adults, it may be more commonly detected in patients with underlying conditions.

https://www.medpagetoday.com/infectiousdisease/generalinfectiousdisease/100632

Targeted Combo Flops as First-Line Treatment in Advanced Breast Cancer

 A novel combination failed to improve the clinical benefit rate (CBR) in advanced triple-negative breast cancer (TNBC) compared with chemoimmunotherapy, a randomized trial showed.

Adding the anti-CD73 antibody oleclumab to durvalumab (Imfinzi) and chemotherapy led to clinical benefit (response plus stable disease) in 43% of patients by 24 weeks as compared with 44% with durvalumab and chemotherapy. Analyses of CBR by PD-L1 and CD73 expression status also showed no significant difference between the treatment groups.

Durvalumab-chemotherapy without oleclumab had a numerically better progression-free survival (7.7 vs 6.0 months), reported Laurence Buisseret, MD, of Institut Jules Bordet in Brussels, at the European Society for Medical Oncology (ESMO) annual congress.

"The optimal chemotherapy duration with immunotherapy needs to be further investigated, and new therapeutic combination approaches are needed," she said. "Ongoing translational research aims to better understand the mechanisms of response and to identify predictive biomarkers of response."

The results contrasted with those from recent studies in unresectable/metastatic non-small cell lung cancer (NSCLC), wherein the addition of oleclumab boosted the CBR from less than 60% with durvalumab-chemotherapy to more than 80%. During a post-presentation discussion, Buisseret pointed out that NSCLC and TNBC have different molecular biology, emphasizing the need to identify biomarkers to guide the use of targeted therapies such as oleclumab.

Buisseret reported primary findings from the randomized phase II SYNERGY trial to evaluate chemoimmunotherapy with or without oleclumab as initial treatment for metastatic TNBC (mTNBC). The trial originated as part of an ongoing search for strategies to improve the efficacy of immunotherapy in mTNBC. One such strategy is to target immunosuppression in the tumor microenvironment, in this case, by focusing on adenosine.

"Tumors are proficient at converting ATP into immunosuppressive adenosine, which activates the A2 receptor on immune cells to induce several highly immunosuppressive functions," she said. "Two enzymes that are key to degrading ATP into adenosine are CD39 and CD73. In breast cancer, CD73 is overexpressed in the TNBC subtype and is associated with worse outcome."

In preclinical models, the combination of an adenosine-pathway inhibitor and a PD-1/L1 inhibitor enhanced immune response, Buisseret continued. In a preliminary clinical trial in patients with mTNBC, adding oleclumab to durvalumab and chemotherapy did not improve response, but the trial was underpowered to assess efficacy.

SYNERGY involved 127 patients with previously untreated locally advanced or metastatic TNBC and no prior exposure to an immune checkpoint inhibitor. All patients received paclitaxel-carboplatin chemotherapy and were randomized to durvalumab alone or with oleclumab. The primary endpoint was CBR at 24 weeks.

The study had an accrual target of 136 patients, which would provide statistical power to detect an improvement in CBR from 40% to 60% at 24 weeks. The trial ended early after an interim analysis met criteria for futility. At data cutoff, the study population had a median follow-up of 13.2 months.

When the trial ended, neither the objective response rate nor CBR differed significantly between treatment arms.

Biomarker status was not an inclusion criterion. Immunohistochemistry results showed that a little more than half of the patients had PD-L1 expression ≥1% (positive), whereas one-fourth to one-third of the patients tested positive for CD73.

An analysis of CBR by biomarker status showed no significant difference between groups with PD-L1-positive or negative tumors or CD73-positive or negative status (P=0.98 to P=0.22). The oleclumab regimen performed numerically better in patients with PD-L1-negative and CD73-positive tumors.

Adverse-event rates, overall and grade 3/4, were similar between the treatment arms.

"The trial is clearly negative. We also don't see a signal with regards to CD73 expression and we don't see a signal in progression-free survival," said ESMO invited discussant Peter Schmid, MD, of University College London. "The addition of oleclumab in an unselected triple-negative breast cancer population clearly did not have a benefit and did not improve the efficacy of chemotherapy and a checkpoint inhibitor. The adenosine pathway is complex. There are several determinants and two receptors. There is overlap with other pathways. Unfortunately, we don't have an optimal biomarker, so we can't really select patients. Patient selection strategy at this point in time for clinical development is not quite clear. CD73 might not be optimal."

Disclosures

The SYNERGY trial was supported by AstraZeneca.

Buisseret disclosed relationships with AstraZeneca.

Schmid disclosed no relationships with industry.

Primary Source

European Society for Medical Oncology

Source Reference: Buisseret L, et al "Primary endpoint results of SYNERGY, a randomized phase II trial, first-line chemoimmunotherapy trial of duvalumab, paclitaxel, and carboplatin with or without the anti-CD73 antibody oleclumab in patients with advanced or metastatic triple-negative breast cancer" ESMO 2022;nAbstract LBA17.

https://www.medpagetoday.com/meetingcoverage/esmo/100637

ESMO: TIL therapy improves on Yervoy in melanoma trial

 A personalised cell therapy based on tumour-infiltrating lymphocyte (TIL) cells has been shown to be more effective at improving progression-free survival than Bristol-Myers Squibb’s immunotherapy Yervoy in patients with advanced melanoma.

It is the first time that a cell therapy for solid tumours has been tested in a phase 3 trial, and the first time that the approach has been directly compared with standard second-line immunotherapy in melanoma.

With the results in hand, the developers of the therapy – from the Netherlands Cancer Institute and Norway’s National Center for Cancer Immune Therapy – say they now intend to file for regulatory approvals in Europe before the end of the year, without a commercial partner “to try to ensure that it remains affordable.”

The M14TIL trial involved 168 patients with stage 3c to 4 melanoma that was too advanced to be treatable with surgery, most of whom (89%) had failed earlier treatment with PD-1 inhibitors like BMS’ Opdivo (nivolumab) or Merck & Co’s Keytruda (pembrolizumab). They were randomised to either TIL treatment or Yervoy, a CTLA4 inhibitor.

The treatment involved harvesting TILs from a biopsy sample taken from a patient’s tumour and growing them in the lab for three to six weeks to expand their numbers.

The patient then receives chemotherapy to reduce regulatory T cells that can put a brake on immune responses to tumours, as well as immune-boosting cytokine interleukin-2, before the TILs are then reinfused into the patient intravenously.

The rationale is that TILs are already primed to attack malignant cells, so providing them in larger numbers should boost their anti-tumour activity.

NCI investigator John Haanen told the ESMO congress that TIL therapy improved PFS compared to Yervoy by 50%, 7.2 months versus 3.1 months with Yervoy, which was a significant improvement.

The therapy had an overall response rate of 49%, with 20% compete responses, compared to 21% and 7% respectively with BMS’ drug, and the investigators are now following the patients to see if there is a significant difference between the groups on the more stringent measure of overall survival.

Health-related quality of life scores were also higher in patients treated with TIL than Yervoy, said Haanen, and no new safety issues were found with the cell therapy, which can be hard to tolerate with grade 3 or higher adverse events occurring in all patients treated.

“The side-effects are well manageable and most resolve by the time patients leave the hospital after their TIL therapy,” said Haanen, adding that that most are related to the chemotherapy and IL-2 that patients receive as part of the TIL regimen.

While first-line immunotherapy with PD-1 inhibitors can be very effective, a sizeable proportion of patients don’t respond to them, and treatment options then become limited.

Cell-based therapies based on CAR-T cells are already well-established for haematological cancers, but are not so effective against solid tumours because they do not readily pass into tumours from the blood. Other approaches such as genetically engineered T cell receptor (TCR) therapies are being developed for solid tumours, but like TILs are still at the experimental stage.

TIL is a new paradigm for treating cancers and, as these results clearly demonstrate, it’s efficacious and feasible at large scale,” said George Coukos, Lausanne University Hospital, who was not involved in the study.

“The findings raise hopes for the management and potential cure of metastatic solid tumours.”

https://pharmaphorum.com/news/esmo-til-therapy-improves-on-yervoy-in-melanoma-trial/

I-Mab: Positive Phase 2 Data of Lemzoparlimab Combo with Azacitidine in Myelodysplastic Syndrome

 I-Mab announced encouraging data from its Phase 2 clinical trial (NCT04202003) of lemzoparlimab (also known as TJC4) in combination with azacitidine (AZA) in patients with newly diagnosed higher risk myelodysplastic syndrome (HR-MDS), presented in an oral presentation on September 10 at the European Society for Medical Oncology (ESMO) Congress 2022.  The open-labeled Phase 2 clinical trial is designed to investigate the efficacy and safety of lemzoparlimab in combination with AZA in patients with newly diagnosed HR-MDS. A total of 53 patients were enrolled as of March 31, 2022, receiving lemzoparlimab at a weekly dose of 30 mg/kg intravenously (IV) and AZA at 75 mg/m2 subcutaneously (SC) on Days 1–7 in a 28-day cycle. Top-line data showed that for patients who began treatments 6 months or longer prior to the analysis (n=15), the overall response rate (ORR) and complete response rate (CRR) was 86.7% and 40% respectively.

For patients who began treatment 4 months or longer prior to the analysis (n=29), the ORR and CRR was 86.2% and 31% respectively. While the study enrolled more patients with worse baseline conditions due to underlying disease (74% of patients had grade =3 anemia and 51% of patients had grade =3 thrombocytopenia), the results showed that lemzoparlimab combined with AZA was well-tolerated and the safety profile was consistent with AZA monotherapy. Decreased red blood cells, measured as hemoglobin, and decreased platelets are major causes of morbidity for patients with HR-MDS and the median hemoglobin and platelet levels for patients on study increased in response to treatment. Of the 29 patients who were dependent upon blood transfusions at baseline, 9 patients (31%)  became transfusion independent at the time of analysis. Furthermore, the majority of CR patients showed reduction in variant allele frequency (VAF) of MDS-related gene mutation including TP53, TET2 and RUNX1, with 56% achieving minimal residual disease negativity (=10-4) by flow cytometry. These data are consistent with the anti-leukemic activities and expected drug safety of lemzoparlimab.

https://www.marketscreener.com/quote/stock/I-MAB-95388118/news/I-Mab-Announces-Positive-Phase-2-Data-of-Lemzoparlimab-in-Combination-with-Azacitidine-in-Patients-w-41744644/

Puma: Updated Findings from the Phase II Trial of Neratinib for Cervical Cancer at ESMO

 Puma Biotechnology, Inc. (NASDAQ: PBYI), a biopharmaceutical company, announced the presentation of updated findings from the Phase II SUMMIT basket trial of neratinib for HER2 (ERBB2)-mutant, metastatic cervical cancer at the 2022 European Society for Medical Oncology (ESMO) Congress, currently taking place in Paris, France. The poster (#559P) entitled, "Neratinib in HER2-mutant, recurrent/metastatic cervical cancer: updated findings from the phase 2 SUMMIT basket trial,” was presented by Claire F. Friedman, M.D., Melanoma and Immunotherapy Service, Memorial Sloan Kettering Cancer Center, on September 11 at 11:10 a.m. CEST.

https://www.marketscreener.com/quote/stock/PUMA-BIOTECHNOLOGY-INC-32676238/news/Puma-Biotechnology-Presents-Updated-Findings-from-the-Phase-II-SUMMIT-Basket-Trial-of-Neratinib-for-41747491/