The expansion of Bruton tyrosine kinase (BTK) inhibitors in the treatment of patients with mantle cell lymphoma (MCL) has led to unique combinations that have resulted in improved progression-free survival (PFS) compared with standard-of-care therapy. These novel combinations have demonstrated promising efficacy in patients who have significant unmet needs. At the same time, BTK inhibitors have refined the use of autologous stem cell transplant (ASCT). Recent findings that stratify the use of BTK inhibitors in combination with ASCT were explored during major medical conferences in 2022.

In younger, fit patients, standard of care for patients with MCL consists of cytarabine, followed by ASCT and rituximab (Rituxan) maintenance.1 In patients who are less fit, the standard-of-care regimen consists of less intense immunotherapy, such as the combination of bendamustine-rituximab, followed by rituximab maintenance therapy.2

Now recent findings from the phase 3 TRIANGLE study (NCT02858258) presented at the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition have suggested that adding the BTK inhibitor ibrutinib (Imbruvica) to standard chemoimmunotherapy induction, followed by ASCT and maintenance with ibrutinib for 2 years improved outcomes compared with chemoimmunotherapy and ASCT alone.3

Based on failure-free survival, the combination of ASCT plus ibrutinib is significantly superior to ASCT alone, lead author Martin Dreyling, MD, said during a presentation of the data. ASCT is not superior to ibrutinib without ASCT. Currently, there [are] no decisions about whether autologous stem cell transplant adds to ibrutinib, but certainly right now toxicity favors ibrutinib only. Dreyling is a professor of medicine and head of the Lymphoma Program in Medical Clinic III at Grosshadern Clinic at Ludwig-Maximilians-University in Munich, Germany. The open-label 3-arm trial (N=870) randomly assigned patients to arm A, arm B, and arm C. All 3 arms received 3 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine [Oncovin], and prednisone)/R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin).

In arm A (n=288) following R-CHOP/R-DHAP, patients underwent ASCT and observation. In arm B (n=292), patients underwent ASCT, followed by 2 years of ibrutinib maintenance and observation. The third arm (n=290) was treated with 2 years of ibrutinib and observation. Patients in all 3 arms received rituximab maintenance (58% in arm A, 57% in arm B, and 54% in arm C). The trial was designed to detect an HR of 0.60 and 1-sided of 0.01665, powered at 90%.

The median age of patients was 57 years (range, 27-68), and most patients (76%) were male. Overall, baseline characteristics were balanced across all 3 arms.

The 3-year failure-free survival rate was 72% with standard induction and ASCT vs 88% with ibrutinib added to induction, ASCT, and 2 years of ibrutinib maintenance (HR, 0.52; P=.0008). Investigators reported that the 3-year overall survival rate (OS) was 86% in arm A, 91% in arm B, and 92% in arm C.3

The objective response rate (ORR) after induction therapy was determined to be 94% in arm A, and patients had a complete response (CR) rate of 36%. When combining the findings from both arm B and arm C (n=559), the ORR was 98% and the CR rate was 45%.3

Dreyling said the CR rates were comparable to other US-based trials and noted that, This [study] is CT based. It is not PET [positron emission tomography]CT based. It is in line with previously published data [using this method], and when we looked at other induction regimens, this is highly comparable.

To further refine the use of ASCT, in the phase 3 SHINE study (NCT01776840), older patients with MCL who were not candidates for intensive chemotherapy or ASCT because of toxicities received ibrutinib with bendamustine-rituximab and rituximab maintenance.4 The patients were stratified by low-, intermediate-, or highrisk disease based on the MCL International Prognostic Index and randomly assigned to receive ibrutinib (560 mg daily) or placebo, plus 6 cycles of bendamustine (90 mg/m2) and rituximab (375 mg/m2).

During the 2022 American Society of Clinical Oncology Annual Meeting, Michael Wang, MD, reported on data showing that at a median follow-up of 84.7 months, treatment with the ibrutinib-based regimen (n = 261) induced a median PFS of 6.7 years (80.6 months) compared with a median of 4.4 years (52.9 months) in the placebo-based arm (HR, 0.75; 1-sided P = .011). This was a 50% improvement compared with placebo and standard of care, Wang noted.

I think this is huge progress [in the MCL landscape], Wang, lead study author and Puddin Clarke Endowed Professor, Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center in Houston, said in an interview with Targeted Therapies in Oncology.

Transplant will not be replaced totally, but I think its use will decrease dramatically based on this study.

The median age of the patients at study entry was 71 years (range, 65-87). Additional results demonstrated a CR rate of 65.5% in the ibrutinib arm and 57.6% in the placebo arm (P = .0567). However, there was no statistical significance in OS between the 2 treatment arms (P = .648).4

Wang said that based on findings from SHINE, in the frontline setting for patients older than 65 years, the combination of ibrutinib, bendamustine, and rituximab will be useful.

Despite its benefits, patients treated with BTK inhibitors will eventually experience resistance, so the search for next-generation BTK inhibitors continues. Clinicians can look towards the approval of pirtobrutinib (Jaypirca) for relapsed or refractory MCL after at least 2 lines of systemic therapy.5 Efficacy was based on findings from the phase 1/2 BRUIN study (NCT03740529), which also explored unique combinations explored during the 2022 ASH meeting.

Updated findings from the BRUIN study demonstrated durable efficacy for pirtobrutinib.6 Previously treated patients with B-cell malignancies were eligible to participate in which pirtobrutinib monotherapy was given in either the dose-escalation or dose-expansion portion of the multicenter study.

In 90 heavily pretreated patients with MCL, 77 (86%) received the recommended phase 2 dose of pirtobrutinib (200 mg once daily). The ORR was 58% (95% CI, 47%-88%) and included 18 CRs (20%) and 34 partial responses (PRs; 38%).6

The median duration of response (DOR) at the 12-month follow-up was 22 months (95% CI, 7.5-not estimable [NE]), according to investigators. The 12-month and 18-month estimated DOR rates were 57% (95% CI, 39%-72%) and 52% (95% CI, 34%68%), respectively.6

In the safety cohort that included all patients treated with pirtobrutinib (n=725), study investigators reported that the most common treatment-emergent adverse event (TEAE) of grade 3 or higher was neutropenia (20%; n=143). The most common any-grade treatment-emergent AEs, regardless of attribution, were fatigue (26%; n=191), diarrhea (22%; n=160), and contusion (19%; n=16). Neutropenia was the most common grade 3 or greater TEAE, according to Wang et al. They concluded that the agent was well tolerated with few drug-related toxicities.6

Another noncovalent BTK inhibitor, CG-806 (luxeptinib), is undergoing evaluation in early-phase clinical trials for patients with relapsed/refractory (R/R) hematologic malignancies, including MCL, chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma. Investigators demonstrated that the agent disrupts B-cell receptor signaling and induces metabolic reprogramming and apoptosis in MCL. The investigators noted that targeting BCL2 using CG-806 warrants further exploration.7

The combination of ibrutinib with zilovertamab (NCT03088878) was explored in patients with MCL and CLL in data presented during the 2022 ASH meeting. Results from the dose-finding and dose- expansion cohorts revealed ORRs of 89.3% and 91.2%, respectively, in patients with MCL (n=25) and CLL (n=31).8

We are excited [to see these data] in patients with MCL and CLL who were treated with this combination, lead author Hun Ju Lee, MD, an assistant professor of medicine in the Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center, said in an interview with Targeted Therapies in Oncology.

In the MCL population, investigators reported a median DOR of 34.1 months (95% CI, 13.67-NE).

At the 6-month, 12-month, and 26-month follow-ups, the CR rate was 29.6%, 37%, and 40.7%, respectively.

The median PFS was 35.9 months (95% CI, 17.3-NE) after a median follow-up of 15.1 months, and the landmark PFS rate was approximately 70% at 30 months.8

In a subpopulation of patients with tumors harboring TP53 mutations, the ORR was 83.3% (with 1 CR and 4 PRs), median DOR was 13.84 months (95% CI, 11.3-NE), median PFS was 17.3 months (95% CI, 2.85NE), and landmark PFS rate at 12 months was greater than 80%. In patients whose Ki67 index score was 30% or greater (n=14), the ORR was 85.7%, with 5 CRs and 7 PRs.8

The combination of ibrutinib and ixazomib (Ninlaro) was evaluated in patients with relapsed/refractory (R/R) MCL.9

In the phase 1 portion, patients could be either ibrutinib nave or ibrutinib pretreated. In phase 2, patients were divided into 2 cohorts: ibrutinib nave or ibrutinib pretreated. Investigators noted that the ibrutinib-pretreated cohort was closed early because of slow enrollment.

In the phase 1 portion (n=12), 2 dose levels of ixazomib were evaluated (3 mg and 4 mg on days 1, 8, and 15 of a 28-day cycle) with ibrutinib at 560 mg daily. Treatment continued until disease progression or unacceptable toxicity.

Thirty-five patients who were ibrutinib-nave were enrolled in phase 2. The CR rate was 42.9% (95% CI, 26.3%-60.6%), and the ORR was 77.1% (95% CI, 59.9%-89.6%).

Median DOR was 8 cycles (range, 1-23), with 23% of patients remaining on treatment after a median of 12 cycles (range, 6-19). Twenty-seven patients discontinued treatment because of AEs (n=13), progression (n=9), death due to an AE (n=1), physician discretion (n=1), and treatment delay (n=1).

The primary end point for the phase 2 portion was CR within the first year of the study treatment.9

Grade 3 AEs including hypertension, lymphopenia, neutropenia, thrombocytopenia, rash, syncope, and atrial fibrillation were reported in 1 patient or more. AEs leading to treatment discontinuation included rash (n=2), atrial fibrillation (n=2), and hepatic failure, sepsis, fatigue/anorexia, peripheral neuropathy, muscle spasms, arthralgia, thrombocytopenia, diarrhea, and heart failure (n=1 each).9

Twelve patients with previously untreated MCL were enrolled in a phase 2 study (NCT04783415).10 Acalabrutinib (Calquence) 100 mg was given twice daily, umbralisib (Ukoniq) 800 mg was given daily, and ublituximab-xiiy (Briumvi) 900 mg was given intravenously on days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles. After 6 cycles, patients continued maintenance with oral agents and ublituximab every 2 cycles (planned for 24 cycles).

The primary end point was efficacy as determined by CR rate, and the secondary end point was safety. Enrollment was suspended by the FDA in February 2022 due to general safety concerns with umbralisib and other PI3K inhibitors.11

Because the first 2 patients who enrolled developed grade 3 and 4 aspartate aminotransferase and alanine transaminase levels, the trial design was amended so that umbralisib was given on days 1 through 14 of cycle 1 and days 1 through 7 of subsequent cycles. Four patients were unable to continue taking acalabrutinib because of elevated aspartate aminotransferase and alanine transaminase levels and continued on umbralisib/ublituximab alone.10

All 12 patients achieved CR (ORR, 100%; CR, 100%). As of data presented at the 2022 ASH meeting, 10 patients remained on therapy. Danilov et al concluded that the combination of continuous umbralisib and acalabrutinib resulted in liver function abnormalities but that intermittent dosing of umbralisib was well tolerated.10

BTK inhibitors in combination with cellular therapies such as chimeric antigen receptor (CAR) T-cell therapy are under evaluation in ongoing trials. Whether to use these agents sequentially or concomitantly remains to be determined.12 The TABLE13-16 summarizes a sample of trials that explore the combination of CAR T-cell therapy with BTK inhibitors.

The evolution of BTK inhibitors in MCL has established this class of agent as a mainstay in the R/R setting, and their potential for further benefit continues to be explored. Unique combinationsincluding those that pair BTK inhibitors with targeted therapies or cellular therapies and second-generation agents further enhance the efficacy of BTK inhibitors, and their use remains a backbone approach moving forward.

REFERENCES

1. Le Gouill S, Thieblemont C, Oberic L, et al; LYSA Group. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017;377(13):1250-1260. doi:10.1056/NEJMoa1701769

2. Visco C, Chiappella A, Nassi L, et al. Rituximab, bendamustine, and low-dose cytarabine as induction therapy in elderly patients with mantle cell lymphoma: a multicentre, phase 2 trial from Fondazione Italiana Linfomi. Lancet Haematol. 2017;4(1):e15-e23. doi:10.1016/S2352-3026(16)30185-5

3. Dreyling M, Doorduijn JK, Gine E, et al. Efficacy and safety of ibrutinib combined with standard first-line treatment or as substitute for autologous stem cell transplantation in younger patients with mantle cell lymphoma: results from the randomized Triangle trial by the European MCL Network. Blood. 2022;140(suppl 1):1-3. doi:10.1182/ blood-2022-163018

4. Wang M, Jurczak W, Jerkeman M, et al. Primary results from the double-blind, placebo-controlled, phase III SHINE study of ibrutinib in combination with bendamustine-rituximab (BR) and R maintenance as a first-line treatment for older patients with mantle cell lymphoma (MCL). J Clin Oncol. 2022;40(suppl 17):LBA7502. doi:10.1200/JCO.2022.40.17_ suppl.LBA7502

5. FDA grants accelerated approval to pirtobrutinib for relapsed or refractory mantle cell lymphoma. FDA. Accessed January 30, 2023. http://bit.ly/40oYhYC

6. Wang ML, Shah NN, Jurczak W, et al. Efficacy of pirtobrutinib in covalent BTK-inhibitor pre-treated relapsed / refractory mantle cell lymphoma: additional patients and extended follow-up from the phase 1/2 BRUIN study. Blood. 2022;140(suppl 1):9368-9372. doi:10.1182/blood-2022-159425

7. Thieme E, Liu T, Bruss N, et al. Dual BTK/SYK inhibition with CG-806 (luxeptinib) disrupts B-cell receptor and Bcl-2 signaling networks in mantle cell lymphoma. Cell Death Dis. 2022;13(3):246. doi:10.1038/s41419-022-04684-1.

8. Lee HJ, Choi M, Siddiqi T. et al. Phase 1/2 study of zilovertamab and ibrutinib in mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), or marginal zone lymphoma (MZL). Blood. 2022;140(suppl 1):566-568. doi:10.1182/ blood-2022-167153

9. Cohen JB, Jegede O, Portell CA, et al. Ibrutinib and ixazomib in relapsed/refractory mantle cell lymphoma: Precog 0404. Blood. 2022;140(suppl 1):6487-6488. doi:10.1182/ blood-2022-164710

10. Danilov AV, Muir A, Melgar I, et al. A phase II trial of acalabrutinib in combination with PI3K inhibitor umbralisib and the anti-CD20 antibody ublituximab (AU2) in patients with previously untreated mantle cell lymphoma (MCL). Blood. 2022;140(suppl 1): 3633-3634. doi:10.1182/ blood-2022-159805

11. FDA investigating possible increased risk of death with lymphoma medicine Ukoniq (umbralisib). Accessed January 10, 2023. https://bit.ly/3ZmWZg6.

12. Jacobson CA, Maus MV. C(h)AR-ting a new course in incurable lymphomas: CAR T cells for mantle cell and follicular lymphomas. Blood Adv. 2020;4(22):5858-5862. doi:10.1182/ bloodadvances.2020003391

13. Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382(14):1331-1342. doi:10.1056/NEJMoa1914347

14. Palomba ML, Gordon LI, Siddiqi T, et al. Safety and preliminary efficacy in patients with relapsed/refractory mantle cell lymphoma receiving lisocabtagene maraleucel in Transcend NHL 001. Blood. 2020;136(suppl 1):10-11. doi:10.1182/ blood-2020-136158

15. Wang Y, Jain P, Locke FL, et al. Brexucabtagene autoleucel for relapsed/refractory mantle cell lymphoma: real world experience from the US Lymphoma CAR T Consortium. Blood. 2021;138(suppl 1):744. doi:10.1182/blood-2021-147563

16. Romancik JT, Goyal S, Gerson JN. Analysis of outcomes and predictors of response in patients with relapsed mantle cell lymphoma treated with brexucabtagene autoleucel. Blood. 2021;138(suppl 1):1756. doi:10.1182/blood-2021-153277

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BTK Inhibitors Stretch Frontline Approaches in Mantle Cell Lymphoma - Targeted Oncology

Johannes Schetelig, MD, MSc

In patients with relapsed or refractory acute myeloid leukemia (AML), those who received an allogeneic hematopoietic cell transplant (alloHCT) attained similar overall survival rates compared with those who first received intense salvage chemotherapy to achieve complete response (CR), according to results from the phase 3 ETAL3-ASAP trial (NCT02461537). These findings run counter to the common practice of offering stem cell transplantation only to patients who have achieved CR, suggesting that patients may skip salvage chemotherapy before receiving a transplant. Results were presented during a press briefing at the 64th American Society of Hematology Annual Meeting and Exposition.1

Patients were randomized 1:1 to a remission induction strategy (RIST arm) with 3 g/m2 cytarabine (1 g/m2 for patients >60 years) twice daily on days 1-3 plus 10 mg/m2 mitoxantrone on days 3 to 5 and subsequent alloHCT or to disease control (DISC arm) prior to sequential conditioning and alloHCT.

Findings from the phase 3 clinical trial showed that the primary end point of disease-free survival (DFS) at day 56 was reached by 84.1% of those in the DISC arm (n = 139) and 81.3% of those in the RIST arm (n = 137; P = .047). Although this missed statistical significance against the 1-sided level of 2.5%, the probability that the true success rate in the investigative arm is below the noninferiority margin is only 4.7%, said study author Johannes Schetelig, MD, MSc, of the University Hospital Carl Gustav Carus in Dresden, Germany, in a presentation of the data.

Schetelig said the authors acknowledged that DFS at day 56 is not an accepted surrogate end point following transplantation. At a median follow-up of 37 months, no difference in leukemia-free survival from day 56 (P = .061) or overall survival (OS) from randomization (P = .047) was observed between the DISC and RIST arms.

Our conclusions are that patients with poor response after first induction chemotherapy or first relapse of AML do not benefit from salvage chemotherapy with high-dose cytarabine plus an anthracycline prior to transplantation, Schetelig said.

Watchful waiting and sequential conditioning prior to allogeneic transplantation result in comparable CR rates and OS and may be the preferred option whenever a stem cell donor is readily available. In patients with AML, CR before alloHCT is known to be a favorable risk factor. Intensive chemotherapy can be given prior to alloHCT to try to induce CR, but it is unknown whether those with relapsed or refractory disease derive a benefit from this approach. Sequential conditioning with high-dose cytarabine or melphalan followed by reduced intensity conditioning and alloHCT has resulted in long-term disease control for this population. In the study, the induction chemotherapy comprised high-dose cytarabine and mitoxantrone followed by alloHCT in patients with relapsed or refractory AML. Our hypothesis was that salvage chemotherapy would not provide a net benefit for patients with high-risk AML, Schetelig said.

To test this hypothesis, investigators enrolled adult patients with high-risk AML following first induction therapy or first untreated relapse who were fit for intensive chemotherapy and alloHCT. Patients were required to have a matched sibling donor, a human leukocyte antigen (HLA)- compatible unrelated donor, or an ongoing donor search with 2 potential unrelated donors and an HLA-matching probability of at least 90%.

Study participants were randomly assigned 1:1 to the RIST arm or the DISC arm. Those in the RIST arm received salvage chemotherapy with cytarabine at 3 g/m2 (1 g/m2 for those older than 60 years) twice daily on days 1 to 3 plus mitoxantrone at 10 mg/m2 on days 3 to 5 followed by alloHCT. In the DISC arm, watchful waiting was recommended, but low-dose cytarabine and single doses of mitoxantrone were allowed for disease control. This was followed by sequential conditioning and alloHCT.

The primary end point of the trial was treatment success, which was defined as DFS at day 65 following alloHCT. Investigators sought to demonstrate noninferiority for the DISC arm, with a margin of 5% and a 1-sided level of 2.5%. OS from randomization and leukemia-free survival from day 65 served as key secondary end points.

The median age in the DISC and RIST arms was 61 years. Less than half of patients were female (45% vs 42%, respectively), and most patients had an ECOG performance status of 0 or 1 (88% vs 90%). Patients had active diseasetwo-thirds defined by poor induction response and one-third defined by relapsed AML, Schetelig noted.

In the DISC arm, the median time to transplantation was 4 weeks, and of note, 76% of patients were cared for by watchful waiting only during that period. Sixteen weeks from being randomly assigned, 97% of the intention-to-treat population had undergone transplant.

In the RIST arm, Schetelig noted that every second patient achieved a CR with salvage chemotherapy. The median time to transplantation was 8 weeks. I would like to highlight that most patients who had not achieved a CR still proceeded to transplantation72% after sequential conditioning, he said. In this arm, 93% of patients received transplants by week 17 after random assignment.

The incidence of adverse effects of grade 3 or above was lower in the DISC arm vs the RIST arm, at 23% and 64%, respectively (P<.001). Notably, those in the DISC arm also spent less time in the hospital prior to transplantation vs those in the RIST arm, at a mean of 19 days (range, 7-63) vs 42 days (range, 9-75; P<.001). The mortality rates on day 28 from time of random assignment were 3.6% in the DISC arm vs 1.5% in the RIST arm.

In the DISC arm, 4 patients did not undergo transplant because of death due to sepsis (n=2), leukemia (n=1), or a decision against alloHCT (n=1). In the RIST arm, 6 patients did not undergo alloHCT because of death due to pneumonia (n=3), immune checkpoint blockade (n=1), refractory AML (n=1), or a decision against it (n=1).

Time to discharge and in-hospital mortality did not differ between the 2 arms, Schetelig added. A more general conclusion and forward-looking statement is that the benefit of any treatment [aimed] at better results after allogeneic transplantation by inducing a CR prior to transplantation should be demonstrated in prospective clinical trials, Schetelig said.

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No Survival Advantage When Chemotherapy Is Given Prior to ... - Targeted Oncology

While cryptocurrency may be a fitting investment for some portfolios, you don't need to put your hard-earned cash into speculative investments in order to pursue market-beating returns. If you have money to put into the stock market right now, there are plenty of companies just begging to be bought with tremendous growth potential to tap into in the years ahead.

These are three such stocks to consider adding to your portfolio right now.

Vertex Pharmaceuticals (VRTX 0.23%) is coming off of another robust year of growth in 2022. The company delivered approximately $9 billion on the top line in the 12-month period, paired with earnings of $3.3 billion and operating income of $4.3 billion. These three metrics represented increases of 18%, 42%, and 66%, respectively, from the prior year.

Vertex isn't content to rest on the success of its cystic fibrosis treatments. It's aggressively building out a pipeline of products, primarily targeting various segments of the rare disease drug market, each of which could represent multi-billion-dollar revenue opportunities for the company.

Among some of the most promising candidates in Vertex's pipeline are a rare blood disorder treatment that the company developed with CRISPR Therapeutics (which could be approved as soon as this year), an MRNA-based cystic fibrosis therapy it's working on with Moderna, and a non-opioid drug to treat acute pain. The company also acquired ViaCyte last year, a company that's working on developing stem-cell based treatments for type 1 diabetes.

Vertex's continued footprint in the cystic fibrosis market includes the only medicines currently approved for targeting the root protein malfunction that leads to the genetic illness, and its rapidly evolving pipeline could be set for a wave of several new approvals in the coming years. For these reasons, investors should consider a long-term position in this healthcare stock.

Pinterest (PINS -0.91%) hasn't delivered the mouth-watering growth that some investors became accustomed to in the earlier days of the pandemic, but its business is still demonstrating promise that could yet yield strong returns in the years to come. After a few quarters of unfavorable year-over-year comparisons to peak growth during the earlier part of the pandemic, user metrics are on the upswing, and Pinterest is continuing to monetize new and existing users very well.

For all of 2022, Pinterest reported total revenue of $2.8 billion, up 9% from 2021, with average revenue per user coming in 10% higher than the prior year. The company closed out the year with 450 million monthly active users, up 4% compared to 2021. And while Pinterest reported a net loss for the 12-month period, it turned back to profitability in the final quarter of the year, generating GAAP net income to the tune of $17 million for the three-month period.

Pinterest remains an incredibly attractive platform for companies to advertise on, with the bulk of all its revenue coming from ad dollars spent by both small businesses and large merchants. Companies won't be able to scale back on ad spend indefinitely. As economic conditions improve, Pinterest's continued acquisition of users and the image-centric model of its platform will build upon a foundation that can continue to draw consistent ad spending, flowing back to the tech stock's top and bottom lines, and into favorable shareholder returns.

Chewy (CHWY 3.07%) is rapidly expanding its potential beyond that of an online pet store, and this has translated to steady growth.

In the third quarter of 2022, the company reported net sales of $2.5 billion, a robust 15% increase from the prior-year period. Meanwhile, its gross margin expanded 200 basis points year over year, while the company pulled in net income of $2.3 million for the three-month period. This followed earnings of $19 million and $22 million in the first and second quarters of 2022, respectively.

Right now, Chewy is investing heavily in building out its business as well as its fulfillment infrastructure, which may weigh on the bottom line now but can reap manifold returns for shareholders in the years ahead. For example, the company is working on building out its network of automated fulfillment centers, which shorten processing times and cut down operating costs overall. It's launched a beta version of a sponsored ads program that would allow pet vendors to market to buyers on the Chewy platform.

The company also recently announced the upcoming launch of additional pet health insurance plans, and its first private label pet supplement line. The pet health insurance and non-prescription pet wellness industries alone represent respective addressable markets of $10 billion and $2.4 billion. Given the varied sub-sectors of the broader pet industry, Chewy could still be in the very early stages of its growth story -- a compelling buying proposition for long-term investors.

Rachel Warren has no position in any of the stocks mentioned. The Motley Fool has positions in and recommends CRISPR Therapeutics, Chewy, Pinterest, and Vertex Pharmaceuticals. The Motley Fool recommends Moderna. The Motley Fool has a disclosure policy.

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3 Growth Stocks With More Potential Than Any Cryptocurrency - The Motley Fool

Michael J. Fallon, MD, radiation oncologist, University of Wisconsin Carbone Cancer Center, discusses supportive care considerations for patients with relapsed/refractory multiple myeloma.

The use of infection prophylaxis continues to evolve with the addition of new therapies, such as anti-BCMA CAR T-cell therapies and bispecific T-cell engagers, since these agents have different effects on the immune system that clinicians are still working to understand, Fallon says. Although the National Comprehensive Cancer Networkguidelines have started to integrate the use of infection prophylaxis with these agents; however, the current recommendations only fit specific conditions for a patient, and more clarity is needed to know when this intervention is appropriate, Fallon explains. In the past, supportive care considerations for patients who received an autologous stem cell transplant were well defined, and improvements to guidelines will be made for newer therapies, according to Fallon, who adds that, in general, patients have less infections with T-cell redirecting therapies compared with other treatments.

Immunizations continue to be a cost burden to patients. For example, patients within the Medicare population are only allowed 2 lifetime doses of a pneumococcal injection, and patients with relapsed/refractory multiple myeloma will likely need up to 4 injections, Fallon explains. For patients who are post transplant, they may require up to 6 injections, and oftentimes, these patients will need to pay out of pocket for these vaccines, Fallon says.

Additionally, tertiary centers will provide some of these injections; however, patients must also rely on the local community hospitals and clinics to provide the injections, Fallon explains. Coordinating these series of vaccines between different health-care systems can also present a challenge for patients with multiple myeloma, Fallon adds.

Bone health remains the most impactful adverse event (AE) for patients with relapsed/refractory multiple myeloma, as they can experience walking difficulties, pain, and numbness, Fallon says. These AEs can be detrimental to a patient's quality of life. It is important that clinicians remain vigilant with medications to maintain bone health medications and ensure fractures do not happen, Fallon concludes.

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Dr. Fallon on Supportive Care Considerations in R/R Multiple ... - OncLive

The bispecific antibody teclistamab-cqyv (Tecvayli) showed promising efficacy and safety in patients with relapsed/refractory multiple myeloma (MM) with a well-tolerated safety profile in data from the phase 1/2 MajesTEC-1 trial (NCT04557098). These results led to the October 2022 FDA approval of the B-cell maturation antigen (BCMA)-directed, CD3 T-cell engager, for adult patients with relapsed or refractory MM who have received at least 4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

The approval was based on 110 patients among whom the overall response rate was 61.8% (95% CI, 52.1%-70.9%) with a complete response rate of 28.2%. The estimated duration of response rate at 6 and 9 months was 90.6% (95% CI, 80.3%95.7%) and 66.5% (95% CI, 38.8%-83.9%), respectively.2

Teclistamab is a highly effective therapy for relapsed/refractory MM that rivals the efficacy of [chimeric antigen receptor] CAR T-cell therapy, but ultimately is a lot simpler to administer and will be more readily available than CAR T-cell therapies, Alfred L. Garfall, MD, said.

In an interview with OncologyLive, Garfall, director of autologous hematopoietic stem cell transplantation and an assistant professor of medicine at the Hospital of the University of Pennsylvania in Philadelphia, discussed the durability of responses teclistamab elicited and how it will change the treatment regimen for relapsed/refractory MM.

Despite all the progress with new MM therapies that have been developed over the past [couple of] decades, unfortunately most patients are expected to relapse. We need new therapies to address the needs of patients who are progressing despite all the best currently available therapies.

What is impressive about teclistamab is the high response rate as a single agent in patients who have become refractory to the most commonly available therapies for MM. In the patient population studied in a pivotal trial, approximately 65% of patients responded to teclistamab and those responses tended to be very durable [with a] median duration of response of approximately 18 months. That is quite impressive.

Among the therapies that we give on an ongoing basis for MM, there are some specific toxicities in the early week or two of teclistamab therapy. For patients who respond and handle those toxicities as most patients do, there is very little cumulative toxicity. Compared with the typical therapies that are being given to patients in this advanced setting, which often entail multiple agents being given continuously over a long period typically once [the patients] get through the initial couple of weeks, they have very good quality of life on teclistamab with very little cumulative toxicity.

Despite receiving it continuously in many cases for several years, patients usually continue to feel well with very little toxicity that affects quality of life. There are some toxicities to be aware of as patients are exposed to it over time; the main things are immune suppression and risk of infection. In my experience, this is such a breath of fresh air for patients who have been on myeloma therapy continuously for years with sophisticated agents that are much better than chemotherapy but still take their toll after [months] of continuous exposure.

We are used to conventional monoclonal antibody therapies for cancer having a single specificity for target on the surface of the cancer cell and binds to that target. A T-cellengaging bispecific antibody such as teclistamab has 1 arm binding to a cell surface target on the surface of the MM cell, in this case BCMA, but with the other arm it binds to a T cell, CD3. By having that dual specificity, the drug can bring together a myeloma cell and a T cell and force T-cell recognition of the myeloma cell, activating the T cell.

This is a mechanism that was first exploited with a drug called blinatumomab [Blincyto], which is an anti-CD19/CD3-bispecific T-cell engager approved for treatment of acute lymphoblastic leukemia. Teclistamab is the first bispecific antibody approved that exploits [this] mechanism of action but does so in the format of a full-length antibody. That means that it has a much longer half-life and so it can be given with intermittent dosing, as opposed to the requirement for continuous intravenous infusion, which is the case for the prior generation of bispecific T-cell engagers, such as blinatumomab.

With almost any MM therapy you are concerned about immunosuppressive effects, and...this drug does have some immunosuppressive effects. Almost all patients who were on it for [an extended time] develop low IgG, which is expected from the effect of the drug on normal plasma cells. Patients treated at our center have all received intravenous immunoglobulin if theyve been on the drug for long enough to develop low immunoglobulin levels.

It was also clear in MajesTEC-1 that there may be an increased risk of opportunistic infections. There was some pneumocystis pneumonia that was seen on the study and as a result we have started giving our patients pneumocystis prophylaxis. There was even a case of progressive multifocal leukoencephalopathy. These infections often occurred in patients who had been on the drug for a [long time] whose myeloma was under very good control, suggesting that there is an immune suppressive effect of teclistamab. Now, the benefit for these patients was clear in terms of their control over myeloma and many of these infections can be [potentially] prevented with measures such as pneumocystis prophylaxis.

Teclistamab is going to be a workhorse for us and patients with heavily relapsed/ refractory disease, in line with its FDA approval. [With] the availability to give it quickly and the excellent safety and efficacy profile, it will be the therapy of choice for many patients in those late lines of therapy. This will be easier for centers to use compared with the complexity of CAR T-cell therapies, even if [those] are a bit more potent.

There is also potential with teclistamab fixed-duration therapy, especially if it is used earlier [during] MM therapy. So far in the clinical trials, it has been given [via] continuous dosing, but we have all had patients who have had to stop it for one reason or another, often for infection. In those patients, at least my experience is that they seldom progress after it stopped even for many months. That raises the possibility that patients could receive fixed courses of this drug, especially earlier on in MM therapy and get the best of both worldsthe upside of its potent antimyeloma activity without the downside of infection risks that may come with long-term exposure.

See more here:
Teclistamab Demonstrates Exciting Efficacy in Relapsed or ... - OncLive

Guest writer Gary Conkling started writing stories as a child and publishing them on his own hand-cranked printing press. Little did he know digital technology would make it possible to repeat the task asan adult by publishing his own blog, Life Notes. He is a journalist by trade who has worked in the trenches of public affairs at the federal, state, regional and local levels. But he also is an observer of life occurring around him. This piece is from his blog, found at https://garyconklinglifenotes.wordpress.com.

Science can be described as the continuous study of what we dont know but wished we did.

Thats why science is discomfiting for humans who believe they know all the answers. Scientists like answers, too, but mostly because they raise even more questions.

At its core, science thrives on exploration, from ancient civilizations digging ditches to redirect water and clambering into boats to see whats over the horizon, and in more recent times from dissecting cadavers to understand human anatomy to discovering the connection between sewage and pathogens.

Mankind has long stared into the sky to see whats out there and understand how it affects Earth. Sky explorers continue making discoveries such as black holes.

Despite their name, black holes are actually dense objects with intense gravitational fields that make it hard for objects and light to escape.

Astronomers believe, at least for now, that jumping into a black hole in space is a one-way trip. But no one knows for sure because we lack the means to reach a black hole since the closest one is 1,600 light years away.

Humans have intuitively understood the importance of the sun to life on Earth. What astronomers have learned is that our sun is a very old ball of energy that holds 99.8 percent of our solar systems mass.

Astronomers predict the sun will burn through its existing hydrogen supply and then expand, engulfing Mercury, Venus and eventually Earth on its journey to becoming a giant red star. Luckily, astronomers estimate the sun has enough hydrogen to keep burning for another 5 billion years.

The science of cells is even more jaw-dropping. Biologists believe cells are the fundamental unit of what we call life. This had led to the scientific fields of cellular and molecular biology.

These biologists now routinely uncover new knowledge about genetics, immunology and neurobiology by learning the relationships within cells of DNA, RNA and protein synthesis.

There are parallel scientific discoveries regarding atomic matter and its properties that govern space, time, energy and matter in the observable universe.

Scientists have uncovered the existence of what physicists call antimatter, which consists of antiparticles with the same mass as matter but with the opposite sign. What sounds like worthless knowledge is actually critical to medical tomography, better known as PET scans.

Quantum mechanics is perhaps the most disruptive discovery by physicists.

Albert Einsteins insight gave us the theory of relativity, but he was never able to combine it with a provable field theory. Einstein wanted to believe how our universe operates was predictable through direct observation.

Physicists have learned matter and light at atomic and subatomic levels have predictable patterns that can be harnessed in things such as integrated circuits, but also can be altered by random events. The course of Earth and its universe is not a foregone conclusion.

That was demonstrated when NASAs DART spacecraft successively slammed into an asteroid, redirecting it onto a new course. This was planned intervention.

At the quantum level, most intervention is unplanned and often unnoticed. Our best evidence of this randomness is human disease, which may affect some people but not others, even among family members.

Scientists examining a random meteorite made a surprising discovery. Even though the meteorite consisted of nickel and iron, common minerals on Earth, they had cooled a million years or so in space, congealing into something not found on Earth tetrataenite.

It turns out tetrataenite is ideal for high-end magnets used in electric vehicles and space shuttle turbines. And scientists have figured out how to replicate tetrataenite in laboratories, which holds the prospect of displacing rare earths that must be mined and processed.

Science may seem like it has reduced life to a soulless existence. Atoms, antimatter and black holes dont provide satisfying stories about life, survival or after-life. In fact, science challenges many religious beliefs, ancient myths and human historical accounts.

Challenging what some accept as truth doesnt need to shatter a belief in a greater power. Scientists have uncovered a great deal about how our universe works but not how it all got its start. The Big Bang Theory explains how the universe is behaving, not why the Big Bang occurred.

What we know is that scientists discover a lot of things that travel well in our everyday lives.

Space exploration best exemplifies the upside of science. In support of space travelers, NASA and various corporations have innovated devices now commonly used in terrestrial life, such as air purifiers, workout machines, flame-retardant clothing, camera phones, invisible braces, solar cells, better tires and baby food.

Scientists may be on to an even more novel, climate-friendly ideas, such as chicken meat without chickens, which the Food and Drug Administration has just given the nod to go forward to a market near you. Slaughter-free, lab-grown chicken meat, referred to as cultivated meat, originated with California cardiologist Dr. Uma Valeti, who was inspired by stem cells used to repair human hearts.

If you can grow heart cells, Valeti reasoned, you can grow chicken meat. Ten years later, he was proven right.

A taste-tester who tried his cultivated meat commented, It tastes like chicken. Valetis quick response, It is chicken.

Thats why chicken brands are salivating to get his laboratory recipe. And its why science can defy everyday logic and understanding.

Brian Greene, a professor of physics and mathematics, is renowned for his breakthrough discoveries in superstring theory, which is an attempt to model fundamental forces of nature as vibrating super-symmetrical strings. Its basically an effort to resolve the theory of relativity with the realities of quantum physics.

However, Greene ventures into a more problematic field the meaning of the universe.

In his latest book, Until the End of Time, Greene uses scientific knowledge to trace the origin of the universe and the human place within that universe. He writes in his preface: Although obscured by mist here and fog there, the panorama is becoming sufficiently clear that we cogitating creatures can glean more fully than ever before how we fit into the grand expanse of time.

Greene wrote that before he knew about chicken meat without chickens.

People with religious beliefs often view science as anti-religious, even as an attack on religion. The tension between scientific inquiry and religious zealotry is real. Scientists focus on questions while zealots settle for answers, sometimes based on dubious evidence or misconstrued history.

There is a path through the tension, though. Scientists dont have to dismiss a greater force and zealots have to rely on faith rather than crypto-facts.

We could someday figure out how the universe truly works, but still never know how it came to be. The desire and for many the desperate need to know there is something larger out there larger than life as we know it can yield an emotional calm and an enhanced ability to deal with very real and present distress.

It also would help if scientists and zealots played by the same rules.

Questions are not disbelief. Probabilities are safer to cling to than facts in assessing the universe. The scientific method and faith are not incompatible.

The branch of science we call archaeology has unearthed the remains of creatures long ago gone extinct and capable civilizations that vanished.

Contemporary religions rarely acknowledge their existence or their successes and failures. Their religions and gods are reduced to pagan rites, despite their reigns that lasted for centuries and may have grown out of the early struggles of post-evolutionary humans.

Their achievements in building grand temples and practical waterworks are overlooked behind the smudge of time covering their history-revealing wall paintings and rock carvings. Their migrations are just lost legends. But like space, we are learning little by little about our forebears on Earth.

It was just 75 years ago that scientists in a New Jersey lab invented the transistor, which created the foundation for what we now call the Digital Age and a fierce global competition to manufacture advanced semiconductors.

The US Department of Energy just announced a scientific breakthrough to mimic the sun by using nuclear fusion to create more energy than it consumed, raising the prospect of a limitless zero-carbon energy source to replace fossil fuels in the battle against climate change.

Science isnt perfect. Neither is our pantheon of perceptions about God.

Believing in something larger than our human selves is something scientists and people of faith have in common. If both were honest, they would admit they have more questions than answers and that faith can help people abide lifes travails.

Science isnt perfect. Religion isnt infallible.

Another point of mutual intersection between science and religion is history. Galileos proclamation that Earth circles the sun turned him into a religious pariah, but opened the window to a more accurate picture of our universe. Think how limited our world would be if we still clung to the belief Earth was flat?

In 1910, zoologist George Murray Levick went to Antarctica to study a penguin colony. Through photography, he observed male birds having sex with other male birds.

Fearing blowback, Levick omitted those observations and photographs from his official report, even though same-sex animal behavior and human behavior had been studied as far back as the 1700s.

Homosexual and bisexual animal behavior has since been chronicled and studied in more than 1,000 species, including mammals. Ironically, the prevalence of homosexual animal behavior conflicts with Darwinian evolutionary theory that stressed reproductive ability as critical to survival.

Today scientists still arent certain what leads to homosexuality. One thing is scientifically known, though: Homosexuality and bisexuality arent moral choices.

They could even be in some species a key to their evolutionary success. Do we have to wait a century or longer to recognize homosexuality can be as determined as human DNA? Couldnt scientists and religious believers agree we have more consequential things to worry about in our world?

Finally, science can inform us about history. Vaccination saves lives. People with black skin arent mentally inferior. Females can be as accomplished as men in operating rooms and sports fields. And yet cult-like groups make false claims about vaccines, women continue to be oppressed by patriarchies and Black people remain undervalued much of this in the name of quasi-religious doctrines.

Humans face massive challenges climate change, artificial intelligence and gene-editing technology. These challenges, among others, represent opportunities for scientists and moralists to cooperate and point to directions that are humane in the face of fundamental change.

We should be at the point where we can say scientists arent always right, and neither are religious leaders. We all have a lot to learn about the human condition. And we have a long way to go to improve the human condition for everyone, including suffering or impoverished people.

Surely that could be a mutual rallying point for scientists and religious leaders. All it would take is some humility that we may never know everything to know in our universe, and that a dose of genuine faith can do more good than harm.

More:
Conklin: Where science and religion intersect - News-Register

By Jim ThompsonHCP columnist

Elliott Winton came into my life unexpectedly around Valentines Day, 2000 when I was diagnosed with Non-Hodgkins Lymphoma. We usually have an appointment to see each other this time of year, and I just saw him again on Feb. 13.

He is in his early 80s, and I am 72. Back when we met, he was in his 50s in the prime of his career, and I was 49. Today, he works at Emorys Winship Cancer Center on Mondays and Grady Hospital (the Saint Elsewhere of Atlanta) on Tuesdays. He is not accepting new patients.

I have written about our travels together before, but I think it is appropriate to relate them again, if for no other reason than to encourage others who have had surprises since the last time I related this journey. Dr. Winton tells me I am in a select group only a few of his patients have stayed around so long, despite the great advances in cancer research in the last quarter century. Think how sad that must be for him.

This years reunion felt a bit different. It was as if one of us might not be around for our already appointed get-together next year, at 9 a.m. Feb. 12, 2024. Of course, we should all live each day as if it might be our last.

The winter of 2006-07 was our toughest together. The chemo was messing up my kidneys and Dr. Winton told me I was within hours of being put on dialysis.

Mr. Thompson, you have got to drink more water and pee, pee, pee! I remember him saying one night about 11 p.m. (I have no idea when he slept, he always seemed to be at the hospital).

But I followed his instructions. I thought I would drown. It probably also helped that three doctors, with a deer-in-the-headlights look, came to my room that night and told me they were my renal team and there to start my prep for dialysis by morning if nothing changed. Things changed. I am sure I never drank so much water in 12 hours before or since.

That was also the winter I decided I was not a statistic. In the middle of the night, I would be on my laptop, looking up data and information on Burkitts Lymphoma, the type I had that time. I had an epiphany when looking at the longevity charts. I realized that every dot on those curves represented people, and I decided I would be one of those people out on the end with longevity, not on the other end of that chart.

Laura was a trooper that winter, too. They would try to let me out of the hospital for a few days for each holiday, but I often would not be home more than a few hours before my temperature shot up, and I had to go back in. Despite my protests, Laura would not take no for an answer, and we would be headed back to Emory. From Thanksgiving to Easter, I spent every holiday in the hospital as well as a lot of time in between.

Then there was February of 2017. I knew I was sick again and made an appointment to see Dr. Winton and his sidekick, Jessica Neeley (I cant say enough good things about her, either. I am convinced she has no life outside the Winship Cancer Center).

Laura and I show up, and Dr. Winton does not like what he sees. He wants to do a PET-Scan right now. He starts calling all the CT-Scanner locations in the Emory system. He finds me an opening within an hour at their downtown location (it usually takes a week or two to get an appointment at any of these which speaks to the clout of Dr. Winton).

Laura and I go straight from Dr. Wintons office to the scanner. When I get off the scanner, the technician said, Dr. Winton called and wants you to wait here for a few minutes.

Unusual. In a few minutes, Dr. Winton calls.

Mr. Thompson, dont go home, come back here, we have a bed for you on E6 (the famous cancer floor at Emory hospital) and we are going to admit you right now.

Yes, sir. What else could I say?

That spring and summer, we prepped and I had an autologous stem cell transplant. It had its ups and downs, too, but Dr. Winton had to stand aside and turn me over the bone marrow transplant team. Yet, he and Jessica came to see me several times during that ordeal, even though they were not my official team at the time. They often came on Sunday afternoons when they got their own rounds done early.

Of course, readers of this column know me and know God is an important part of my life. Ive been given, so far, an extra 23 years. I wake up every morning asking the Lord what he wants me to do with these days. I didnt beat cancer. He did, and I need to follow His leading on what to do with all this extra time.

For those of you who read my previous columns on these experiences with a detached, "that is something that happens to others, but have now found it has happened to you" attitude, be encouraged. Your dot on the longevity curves may be at the same place mine has been. But I will be happy to talk to you, no matter where your dot on the curve winds up. See below for how to reach me.

Jim Thompson, formerly of Marshall, is a graduate of Hillsboro High School and the University of Cincinnati. He resides in Duluth, Ga. and is a columnist for The Highland County Press. He may be reached at [emailprotected]

Read more from the original source:
Happy Valentine's Day - The Highland County Press

Stretch the shelf-life of your grapes with these tips.

Larisa Davydova/Getty Images

No matter the variety, grapes make for a delicious snack, especially when theyre spread across a beautiful charcuterie board (theyre of course also delicious in liquid form, if you catch my drift). But grapes also happen to be a pricier produce item, and can spoil quite quickly if not stored properly. It can also be difficult to pick the perfect bunch of grapes since theyre so tightly clustered together.

Still, there are a few things to look out for when examining grapes at the grocery store. Its always important to make sure theyre firm, plump, and attached to the stem. If you pick up a bag with loose grapes rolling around at the bottom, thats a good indicator that they may be quicker to spoil. And while this may seem like common knowledge, you should also avoid grapes that are moldy, watery, and shriveled at the stem. However, if you see a whiteish coating on a bunch of grapes, thats totally fine. Its called bloom, which is a naturally occurring substance that protects grapes from moisture loss.

:13 Foods That (Basically) Never Spoil

Now that you know how to pick out a stellar bunch, keep reading for tips on how to store grapes so you can enjoy them for weeks at a time.

Have you ever walked into someones kitchen and noticed a big, beautiful bowl of grapes on the counter? While grapes may make for a convenient grab-and-go snack when stored this way, this is the quickest way for grapes to lose their moisture and crispness.

Instead, whole grapes should be washed, patted dry, and then stored in a well-ventilated container in the crisper drawer of your refrigerator. This will allow them to last for up to three weeks. Youll want to avoid putting them into an airtight container or plastic bag, since that prevents air circulation. You could also keep whole grapes in the bag they came in if you dont have a proper food storage container.

:How to Store Strawberries So They Won't Spoil Quickly

If you have leftover cut up grapes, theres no need to toss them just yet! Cut grapes can be stored in an airtight container in the refrigerator for up to 48 hours. If you notice the edges start to dry up and brown, thats finetheyre still safe to eat.

Use any leftover cut grapes as a yogurt or oatmeal topping, or as a bite-sized snack.

Yes, you can freeze grapes. And if youve never had frozen grapes, what are you waiting for?! They make for such a quick and delicious snack or dessertbasically like an all-natural, bite-sized freeze pop.

:Does Flour Go Bad? Here's When You Should Replace Your Baking Staples

To freeze, simply rinse and dry your grapes and spread them out on a lined baking sheet. Place them in the freezer for a few hours or overnight, and once theyre frozen, you can put them in a storage container so theyre easily accessible. Just make sure that your grapes arent clumped together on the baking sheet, otherwise they will freeze together (which I guess isnt the worst thing). If youre feeling especially fancy, you can roll your frozen grapes in coarse sugar to add some extra sweetness. Just make sure you enjoy them immediately!

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Read the original article on Real Simple.

See original here:
How to Store Grapes So They Stay Firm and Fresh - AOL

William Haseltine

It is becoming increasingly clear that we have misunderstood SARS-CoV-2, the virus that causes COVID-19. Many people, including some experts in the scientific community, deemed the pandemic over with the release of the mRNA vaccines. The beliefor perhaps it was hope in disguisewas that with the development of the vaccines, we could go back to living our lives as usual, back to a semblance of pre-pandemic normalcy. This simply is not so, as evidenced by surging cases around the world and the continued onslaught of variant after variant.

Even the latest approach, trying to play catch-up with variants by updating our vaccines to match the dominant circulating strain, is a losing game; we will always be one step behind, forced to adapt to the cards we are dealt rather than dictating the playing field. This should come as no surprise. Across the globe, highly skilled influenza researchers have been battling for decades to develop long-lasting, broadly neutralizing flu shots. Although plenty of progress has been made, we still have yearly flu seasons, some of which are plagued by low vaccine efficacyin 2021/2022, the vaccine was only 36% effective at preventing influenza cases requiring medical attention.1

At this point, we seem to have accepted that we will be living with COVID-19 for the foreseeable future; such complacency is very dangerous. Living with the virus is no different from living with a pet lion; there is never any guarantee of safety. We know SARS-CoV-2 can change rapidly, we know it can become far more virulent, and we have no idea of the determinants of pathogenesis.

Our single-minded reliance on vaccines, at the expense of developing novel drug therapies, has left us fighting with one hand tied behind our back. Our current antivirals are anemic at best: they are either no longer effective, like most monoclonal antibodies, or they simply cannot prevent infection in the first place. If we ever hope to control COVID-19, we need to join the battle fully. This means a dramatic increase in resources to fund drug development efforts. The problem is not a lack of tools; it is a lack of political, scientific, and economic will. It is time to change that.

What follows is a summary of the shortcomings of our currently available antiviral drugs as well as a brief overview of some promising, up-and-coming contenders.

1. Monoclonal Antibodies (mAbs)

Monoclonal antibodies are antibodies designed to target a specific antigen or even a specific region of an antigen, usually the spike protein. Once the antibodies bind to the antigen, they either block it from being able to bind to our cells or mark it for destruction by other immune cells. As such, they work well in instances where they correctly match up to the antigen at handsuccessfully neutralizing the virus and inhibiting infectionbut suffer from the same major issues as vaccines: viral resistance and viral mutation.2 With repeat or extended exposure to a certain antibody, SARS-CoV-2 will eventually mutate to escape the immune system, rendering the antibody ineffective and even in the absence of resistance, run-of-the-mill viral mutation can have the same effect.

Monoclonal antibodies come with the additional drawback of needing to be administered intravenously or subcutaneously by a healthcare professional. None of the currently available options come in an oral format, as a pill. This means people with mild-to-moderate diseasenot bad enough to warrant hospitalizationoften do not receive treatment and, while sick, run the risk of infecting others. Practically speaking, monoclonal antibodies simply cannot be used prophylactically; they may help you once youre in the hospital, but they wont be able to stop you from ending up there in the first place.

2. Paxlovid

Paxlovid is a kinase inhibitor that interferes with the main protease (Mpro) of SARS-CoV-2; it is highly efficacious, safe, and is taken orally. Early clinical trial results confirmed its promise, indicating a near-90% reduction in the risk of COVID-19related hospitalizations and deaths.3 Even in a highly vaccinated population, the drug was able to reduce hospitalization or death by 44% in adults over 50 years of age.4 And unlike monoclonal antibodies, viral resistance and viral variation pose less of an issue for Paxlovid because the main protease is a highly conserved region of the SARS-CoV-2 genome. Whereas the spike protein can undergo large structural changes without too heavy of a sacrifice on viral fitness, this is simply not true of the main protease.5

So what are the drawbacks? First on the list is a phenomenon that has been termed Paxlovid rebound. This occurs when, following a full course of the medication and apparent clearance of the virus, symptoms suddenly return. Although this may happen even in the absence of antiviral treatmentsone preprint indicates that up to 10% of infections are followed by a rebound in symptoms and 12% by a rebound in viral levels it is more common in those treated with Paxlovid.6,7 The main limitation facing Paxlovid, however, is its inability to prevent infection.8 As such, it cannot be used in a pre- or post-exposure context, cannot avert onward transmission, and cannot contain the pandemic. It is a great start and points us in the right direction, but it is not the final solution.

3. Remdesivir

Remdesivir is a nucleoside analogue that works by inhibiting RNA-dependent RNA polymerasethe enzyme that builds up viral RNA chains during replication. Despite being a nucleotide analogue, it does not carry the mutagenic risk of molnupiravir; rather than being incorporated into the viral genome and then introducing errors, it works by being incorporated into the viral genome and then stalling the inclusion of any additional nucleosides.

Still, remdesivir suffers from other issues. First and foremost is the problem of low efficacy. Results from the World Health Organization (WHO) Solidarity Trial, a randomized trial that enlisted roughly 3,000 people, concluded that remdesivir has no significant effect on patients with COVID-19 who are already being ventilated.9 For hospitalized patients not requiring ventilation, remdesivir had only a small, nonsignificant effect on death or progression to ventilation.

Another major drawback of remdesivir is the fact it must be administered intravenously across the span of multiple days. As with monoclonal antibodies, this significantly limits its practicality for everyday use. It also means that it cannot be used in a prophylactic capacity.

4. Molnupiravir

Molnupiravir works by inserting errors into the viral genome.10 These errors are then copied during replication, and when enough of them accrue, viral proteins end up with too many mutations to properly function, incapacitating the virus. The main issue facing molnupiravir is low efficacy. It was initially touted to reduce the risk of hospitalization and death by up to 50%, but this number dropped down to 30% by the end of the full clinical trial.11,12 Since then, new data from the largest randomized trial of molnupiravir, which enlisted a total of 26,000 individuals, indicate that molnupiravir offers no reduction in the frequency of COVID-19associated hospitalizations or deaths in high-risk vaccinated adults.13 Whether you take molnupiravir or you take a placebo, your odds are the same.

The low efficacy is further problematized by a dubious safety profile. Owing to a shared intermediate required in both the synthesis of viral RNA as well as human DNAribonucleoside 5-diphosphatemolnupiravir may pose a mutagenic threat to humans: instead of introducing errors only to viral RNA, the drug may also lead to host DNA mutations.14 Long term, this could result in the growth of cancerous tumors and even birth defects, either through mutated sperm precursor cells or if given directly to pregnant women.

Molnupiravirs mechanism of action also carries the risk of spawning new viral variants. Recall that its entire modus operandi is, essentially, destruction via mutation. Certain scenarios, some as banal as a person forgetting to finish their full course of medication, may bring about all of the mutation with none of the destruction. The risk of such viral mutations following treatment with molnupiravir is especially acute in immunocompromised patients, where new variants can form as quickly as a day or two.15

New Drugs, Familiar Mechanisms

Many of the novel COVID-19 drugs making their way through the development and trial pipeline are based on the same broad strategies as the antivirals discussed above. They take advantage of the same viral weaknesses but try to improve on the limitations of their predecessors.

Take, for example, the kinase inhibitor Xocova. Developed by Japanese pharmaceutical company Shionogi, it works in the same way as Paxlovid, by inhibiting the main protease (Mpro) of SARS-CoV-2. Early efficacy data, albeit based on a very small sample size, indicates robust antiviral activity, with a rapid decrease in viral RNA titers compared with placebo.16 That said, time until relief of symptoms was similar between the two groups.

Another group of Japanese researchers developed and tested main protease inhibitors that include fluorine atoms to increase cell membrane permeability and binding affinity for the pocket of Mpro. The team also replaced the digestible amide bond with a surrogate structure to improve biostability. The modified compounds outperformed nirmatrelvir in mouse models.17

Then there is VV116, an oral remdesivir derivative.18 Like its parent compound, it works by inhibiting the RNA-dependent RNA polymerase. Unlike its parent compound, however, VV116 matches Paxlovid in efficacy, enabling clinical recovery from mild-to-moderate COVID-19 in the same amount of time.19 And crucially, where remdesivir must be delivered via injection or intravenous drip, VV116 can be taken orally, expanding its potential reach.

Despite small improvements, such up-and-coming antivirals represent a mostly lateral move. True, they expand our arsenal of treatments against COVID-19 and help decrease the risk of viral resistance, but ultimately they differ from our current antivirals in degree, not in kind. Like Paxlovid, molnupiravir, monoclonal antibodies, and remdesivir, none of them will work prophylacticallythey can only treat, not prevent.

Exploiting Vulnerabilities: Strategies for Prophylactic Drug Design

With an eye toward prevention, its clear we need to diversify our lines of attack against SARS-CoV-2. What follows is a broad overview of strategies that may yield more success in the pursuit of prophylactic antivirals.

COVID-19 begins when SARS-CoV-2 first encounters cells in the upper airway that express a suitable attachment site, the angiotensin converting enzyme 2 (ACE 2). But entry into the target cells requires much more than surface attachment; after the virus has attached itself to ACE2, it still needs to fuse with the host cell membrane in order to inject its genetic material into the cytoplasm, where replication can begin. To fuse with the host membrane, SARS-CoV-2 depends on certain human enzymesfurin, transmembrane serine proteases (TMPRSSs), and cathepsins (CTSs)to cleave its spike (S) protein. Inhibition of ACE2-binding or of membrane fusion blocks viral entry, short circuiting infection before it ever gets a foothold.

Binding and fusion are complex processes with many moving parts, rendering them sites of potential failure. Scientists have begun exposing these vulnerabilities and leveraging them to their advantage.

1. Potential therapies targeting the human ACE2 receptor of the viral spike protein

A massive survey of 2,900 FDA-approved drugs revealed that carvedilol, a beta blocker used to treat high blood pressure and heart failure, may also prove useful against SARS-CoV-2.20 To test its suitability, researchers exposed human lung cells (A549-ACE2) to carvedilol for two hours before infecting them with SARS-CoV-2. After two days of incubation, they checked the cells for the presence of SARS-CoV-2 spike protein, used as a marker of infection. At a half-maximal effective concentration of 4.1M, carvedilol successfully cleared infection. Further, assessment of two large COVID-19 databases indicated that carvedilol-use was associated with a 17% lower risk of a COVID-19 positive test result. Although the exact mechanism of action through which carvedilol inhibits SARS-CoV-2 entry into cells is unknown, the researchers suggest this may happen through disruption of spike proteinACE2 interactions.

Another candidate, aloperine, comes by way of a medicinal plant called Sophora alopecuroides L. Isolated from the seeds of the plant, aloperine and its various derivatives have previously been shown to impair viral entry of HIV-1 and influenza.21 A recent study indicates that aloperines antiviral activity extends to SARS-CoV-2, successfully inhibiting entry into host cells in vitro.22 Compound 5, one of many aloperine-derivatives, proved especially effective, capable of limiting viral entry not only against pseudotyped viruses with the D614G variant of the spike protein, but also against Delta and Omicron variants. Confocal microscopy suggests that compound 5 inhibits viral entry before fusion to the cell or endosomal membrane.

Then there are a variety of ACE2 decoys, which mimic the receptor protein and trick the virus into binding to them instead of binding the real thing.23 Once the SARS-CoV-2 spike protein binds to the decoy, it undergoes irreversible structural changes that prevent it from being able to bind to ACE2 down the line, effectively blocking viral entry. ACE2 decoys come with the added benefit of being broadly-neutralizing; whereas SARS-CoV-2 evolves to escape monoclonal antibodies, evolution selects for ACE2 affinity. Thus, viral resistance to ACE2 decoys would come at the expense of its ability to bind ACE2, impairing infectivity and overall viral fitness. ACE2 decoys remain effective against the Omicron family of SARS-CoV-2.

2. Therapies targeting viral membrane fusion

In addition to fusing with the cell membrane directly, SARS-CoV-2 can inject its genetic material into cells by being absorbed into the cell in a vesicle, a process known as endocytosis, and then fusing with the membrane of the endosome once inside the cell. Obatoclax, an experimental drug for the treatment of cancers, was found to deliver a double strike against SARS-CoV-2, blocking both direct membrane fusion as well as endocytosis; it blocks direct membrane fusion by reducing furin activity and it blocks endocytosis by reducing the activity of cathepsin L.24 In vitro, obatoclax retained its potency against the spike proteins of different variants, including Alpha, Beta, and Delta. The study was performed prior to the emergence of Omicron.

An additional approach to blocking cathepsin Lmediated entry of SARS-CoV-2 involves the use of the RNA-editing tool Genome-wide Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas13. With the help of CRISPR-Cas13, researchers knocked down cathepsin L messenger RNA (mRNA) in the lungs of mice, significantly reducing viral entry.25 To deliver the CRISPR-Cas13 specifically to the lungsleaving cathepsin L untouched in the spleen and the liverthey engineered lung-selective lipid nanoparticles (LNPs). Both prophylactic and therapeutic administration of the lung-specific CRISPR-Cas13dbased therapy effectively inhibits lethal SARS-CoV-2 infection in mice. Significantly, this approach inhibited infection not only against wild-type SARS-CoV-2 and against the Delta variant, but also against SARS-CoV-1, the cause of the 2003 SARS outbreak.

Cathepsin L is one of the two main proteases that SARS-CoV-2 depends on for viral entry into host cells. The other, as mentioned above, is TMPRSS2. A group of German scientists tested nafamostat mesylate, a kinase inhibitor that targets TMPRSS2 and is approved for treatment of pancreatitis in Japan, for its ability to block SARS-CoV-2 infection. Indeed, the compound strongly suppressed viral entry in vitro.26 A separate study, using kinase inhibitors to simultaneously block TMPRSS2 and cathepsin B, yielded similar results, with a reduction of viral load to 0.036% in ACE2-expressing human induced pluripotent stem cells.27 These results held up against multiple variants.

As much as we would like to pretend otherwise, the COVID-19 pandemic does not end where vaccines begin. At least not the current vaccines. XBB.1.5 is just the latest reminder that, as long as SARS-CoV-2 continues to spread and mutate we will continue to see waves of infection.

This is not to say that vaccines do not have their place in the fight against COVID-19, they clearly do, but rather that they are not the panacea that many hoped and that some claimed they would be. Vaccination is one protective strategy, but we cannot put all of our eggs in a single basket. And if we do, we should not be surprised when they end up cracking. Vaccines protect against the worst of COVID-19, but they do so only for a limited duration and against a limited number of variants. This wont change anytime soon.

What can we do to help improve our odds against SARS-CoV-2? We need to actively expand our arsenal of anti-COVID-19 drugs. In particular, it should have dawned on us that we need to develop combinatorial drug therapies that can be used prophylactically, to prevent infection and stop onward transmission. We still do not have a vaccine for human immunodeficiency virus (HIV), for example, but new infections and deaths continue to decline.28 We owe this largely to antiretroviral therapy (ART) and pre-exposure prophylactic (PrEP) medication. Antiretrovirals help those who are HIV positive suppress viral loads to undetectable levels. Undetectable = untransmittable, meaning they cannot pass the virus on to others.29 Similarly, pre-exposure prophylactic (PrEP) medication helps protect those at high-risk of exposure to HIV. As long as it is taken as prescribed, it prevents the virus from taking hold in the body.

If we hope to ever contain SARS-CoV-2, we need to pursue a similar strategy. My recommendation is the following: in the United States, a warp-speed-like project between government, industry, and academia and a minimum of five billion, or up to ten billion, additional dollars per year to fund such collaborations.30 A similar commitment to public health and drug development must be echoed by others, especially the European Union and China. We also need to make sure we have global clinical trial capabilities in place, so that wherever outbreaks occur, we are prepared to test novel drugs on the spot. It is time to fight the battle with both hands, not just one.

References

William R. Haseltine, PhD, is chair and president of the think tank ACCESS Health International, a former Harvard Medical School and School of Public Health professor and founder of the universitys cancer and HIV/AIDS research departments. He is also the founder of more than a dozen biotechnology companies, including Human Genome Sciences.

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Can We Still Contain, and Possibly Eliminate, COVID-19? Yes, and ... - Inside Precision Medicine

What is positron emission tomography (PET)?

Positron emission tomography (PET) is a type of nuclear medicine procedure that measures metabolic activity of the cells of body tissues. PET is actually a combination of nuclear medicine and biochemical analysis. Used mostly in patients with brain or heart conditions and cancer, PET helps to visualize the biochemical changes taking place in the body, such as the metabolism (the process by which cells change food into energy after food is digested and absorbed into the blood) of the heart muscle.

PET differs from other nuclear medicine examinations in that PET detects metabolism within body tissues, whereas other types of nuclear medicine examinations detect the amount of a radioactive substance collected in body tissue in a certain location to examine the tissue's function.

Since PET is a type of nuclear medicine procedure, this means that a tiny amount of a radioactive substance, called a radiopharmaceutical (radionuclide or radioactive tracer), is used during the procedure to assist in the examination of the tissue under study. Specifically, PET studies evaluate the metabolism of a particular organ or tissue, so that information about the physiology (functionality) and anatomy (structure) of the organ or tissue is evaluated, as well as its biochemical properties. Thus, PET may detect biochemical changes in an organ or tissue that can identify the onset of a disease process before anatomical changes related to the disease can be seen with other imaging processes such as computed tomography (CT) or magnetic resonance imaging (MRI).

PET is most often used by oncologists (doctors specializing in cancer treatment), neurologists and neurosurgeons (doctors specializing in treatment and surgery of the brain and nervous system), and cardiologists (doctors specializing in the treatment of the heart). However, as advances in PET technologies continue, this procedure is beginning to be used more widely in other areas.

PET may also be used in conjunction with other diagnostic tests, such as computed tomography (CT) or magnetic resonance imaging (MRI) to provide more definitive information about malignant (cancerous) tumors and other lesions. Newer technology combines PET and CT into one scanner, known as PET/CT. PET/CT shows particular promise in the diagnosis and treatment of lung cancer, evaluating epilepsy, Alzheimer's disease and coronary artery disease.

Originally, PET procedures were performed in dedicated PET centers, because the equipment to make the radiopharmaceuticals, including a cyclotron and a radiochemistry lab, had to be available, in addition to the PET scanner. Now, the radiopharmaceuticals are produced in many areas and are sent to PET centers, so that only the scanner is required to perform a PET scan.

Further increasing the availability of PET imaging is a technology called gamma camera systems (devices used to scan patients who have been injected with small amounts of radionuclides and currently in use with other nuclear medicine procedures). These systems have been adapted for use in PET scan procedures. The gamma camera system can complete a scan more quickly, and at less cost, than a traditional PET scan.

PET works by using a scanning device (a machine with a large hole at its center) to detect photons (subatomic particles) emitted by a radionuclide in the organ or tissue being examined.

The radionuclides used in PET scans are made by attaching a radioactive atom to chemical substances that are used naturally by the particular organ or tissue during its metabolic process. For example, in PET scans of the brain, a radioactive atom is applied to glucose (blood sugar) to create a radionuclide called fluorodeoxyglucose (FDG), because the brain uses glucose for its metabolism. FDG is widely used in PET scanning.

Other substances may be used for PET scanning, depending on the purpose of the scan. If blood flow and perfusion of an organ or tissue is of interest, the radionuclide may be a type of radioactive oxygen, carbon, nitrogen, or gallium.

The radionuclide is administered into a vein through an intravenous (IV) line. Next, the PET scanner slowly moves over the part of the body being examined. Positrons are emitted by the breakdown of the radionuclide. Gamma rays called annihilation photons are created when positrons collide with electrons near the decay event. The scanner then detects the annihilation photons, which arrive at the detectors in coincidence at 180 degrees apart from one another. A computer analyzes those gamma rays and uses the information to create an image map of the organ or tissue being studied. The amount of the radionuclide collected in the tissue affects how brightly the tissue appears on the image, and indicates the level of organ or tissue function.

In general, PET scans may be used to evaluate organs and/or tissues for the presence of disease or other conditions. PET may also be used to evaluate the function of organs, such as the heart or brain. The most common use of PET is in the detection of cancer and the evaluation of cancer treatment.

More specific reasons for PET scans include, but are not limited to, the following:

To diagnose dementias (conditions that involve deterioration of mental function), such as Alzheimer's disease, as well as other neurological conditions such as:

Parkinson's disease. A progressive disease of the nervous system in which a fine tremor, muscle weakness, and a peculiar type of gait are seen.

Huntington's disease. A hereditary disease of the nervous system which causes increasing dementia, bizarre involuntary movements, and abnormal posture.

Epilepsy. A brain disorder involving recurrent seizures.

Cerebrovascular accident (stroke)

To locate the specific surgical site prior to surgical procedures of the brain

To evaluate the brain after trauma to detect hematoma (blood clot), bleeding, and/or perfusion (blood and oxygen flow) of the brain tissue

To detect the spread of cancer to other parts of the body from the original cancer site

To evaluate the effectiveness of cancer treatment

To evaluate the perfusion (blood flow) to the myocardium (heart muscle) as an aid in determining the usefulness of a therapeutic procedure to improve blood flow to the myocardium

To further identify lung lesions or masses detected on chest X-ray and/or chest CT

To assist in the management and treatment of lung cancer by staging lesions and following the progress of lesions after treatment

To detect recurrence of tumors earlier than with other diagnostic modalities

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Positron Emission Tomography (PET) | Johns Hopkins Medicine