Lilly Seeks First-Line KRAS Treatment with AACR Data Release

 Eli Lilly presented the first clinical data on its KRAS G12 inhibitor at the American Association for Cancer Research (AACR) meeting in Orlando on Monday. Lilly investigators said they hoped to differentiate their Phase I candidate from the competitive KRAS space by making it the first to gain approval as a first-line treatment.

Currently approved competitors work as a second-line treatment.

KRAS G12 is a specific genetic mutation in the KRAS oncogene. The KRAS gene produces a protein called K-Ras, which helps to regulate cell growth and division. A mutation in the KRAS gene can lead to the production of a faulty K-Ras protein that is always active, causing cells to grow and divide uncontrollably, resulting in cancer.

The KRAS G12 mutation refers explicitly to a change in the genetic code of the KRAS gene at position 12, where the amino acid glycine is replaced with another amino acid, most commonly aspartic acid or valine. This mutation is commonly found in various types of cancer, including lung, colorectal and pancreatic cancer.

Lilly enters a space already occupied by Amgen’s Lumakras (sotorasib) and Mirati’s Krazati (adagrasib), both approved as second-line treatments for lung cancer. Nevertheless, David Hyman, chief medical officer at Loxo Oncology, told BioSpace the field is “wide open.”

Although Lumakras and Krazati are approved as second-line treatments for lung cancer, along with other investigational agents, Hyman said the field is having challenges advancing into first-line treatment.

Lilly’s Data

Lilly’s 84-patient study tested LY3537982 alone and combined with programmed cell death protein 1 (PD-1) inhibitors, such as Keytruda, in patients with previously treated KRAS G12-mutant advanced solid tumors. The therapy showed preliminary efficacy across all doses of several tumor types, including NSCLC, colorectal cancer and pancreatic cancer, according to a slide presentation at AACR.

Hyman said the efficacy results were similar to those of other KRAS inhibitors combined with PD1 inhibitors currently marketed as second-line treatments. 

In the eight non-small cell lung cancer (NSCLC) patients who had not previously received a KRAS inhibitor, LY3537982 elicited an overall response rate (ORR) of 38% and a disease control rate (DCR) of 88%. In the 14 patients who had previously received a KRAS inhibitor, the results showed an ORR of 7% and DCR of 64%.

In the 20 colorectal cancer patients, the ORR was 10%; DCR 90%. For pancreatic cancer, the ORR was 42%; DCR, 92%. Finally, in “other” (including ovarian and head and neck cancer patients), the ORR was 52%; DCR, 95%.

Hyman also touted LY3537982’s safety profile. Researchers didn’t find the side effects (e.g., diarrhea, liver toxicity) with Lilly’s drug that they have struggled with in competitor assets.

Hyman said that other approved drugs, such as Krazati, are often billed as tolerable, but in reality, that’s not always the case.

“The overall toxicity burden we hear from prescribers, and actually from patients, is such that the regimen is technically tolerable, but not in a way where there’s actually any enthusiasm to use it in that setting, and that matters,” he said.

David Meek, CEO at Mirati, disagreed.

“We believe Krazati is a differentiated product that will become the market-leading treatment for patients with KRAS G12C-mutated cancers based on overall efficacy, tolerability, and its clinically demonstrated CNS activity and combinability with other agents,” he wrote in an email statement to BioSpace.

KRAS Competitors

Mirati and Amgen have attempted first-line trials with mixed results.

Mirati’s drug, combined with Keytruda, shrank tumors in 49% of 53 patients with newly diagnosed KRAS G12C-mutated NSCLC during a Phase II trial published last year. This study examined Krazati as a first-line treatment.

Meanwhile, Amgen’s Lumakras is also approved for KRAS G12C-mutated NSCLC after at least one prior systemic therapy. In June 2022, Amgen touted positive early data from a Phase II trial of Lumakras as a potential first-line treatment for people with KRAS G12 advanced NSCLC, BioSpace reported.

Sumita Bhatta, vice president and global medical therapeutic area head of oncology at Amgen, told BioSpace that making side-by-side comparisons is problematic.

“Cross-trial comparisons cannot be made between KRAS G12 inhibitors,” she said via email.

“As the leaders who brought the first KRASG12C inhibitor, Amgen has several competitive advantages in this market.”

Lumakras is the first and only KRAS G12 inhibitor with once-daily dosing and a proven track record showing its capability to treat KRAS G12-mutated NSCLC in the clinic and the real world, she said. The drug is approved for second-line treatment.

Nonetheless, Lilly still seeks to make first-line status with its research.

“If we’re going to compete to be part of that backbone of therapy, we need to meet the same benefit-risk bar [as chemotherapy], Hyman said. “The idea here is that second-line agents are important advances but not a paradigm shift.”

https://www.biospace.com/article/lilly-seeks-first-line-treatment-in-kras-with-aacr-data-release/

Definitive Healthcare started at Outperform by Blair

 https://finviz.com/quote.ashx?t=DH&ty=c&ta=1&p=d

Biomea Fusion to Present Late Breaking Data from Ongoing Phase 2 Type 2 Diabetes Trial at ADA

 Biomea Fusion, Inc. (“Biomea”) (Nasdaq: BMEA), a clinical-stage biopharmaceutical company dedicated to discovering and developing novel covalent small molecules to treat and improve the lives of patients with genetically defined cancers and metabolic diseases, today announced that it will present new clinical data from the ongoing Phase II portion of its COVALENT-111 trial, which is evaluating BMF-219 as a treatment for patients with type 2 diabetes, in a late-breaking poster presentation at the 2023 American Diabetes Association (ADA) 83rd Scientific Sessions, to be held June 23 – 26, 2023 in San Diego, CA. The company will also host an investor and KOL event during the Scientific Session.

Biomea will disclose additional information about the late-breaking presentation in accordance with ADA’s abstract embargo policies. In addition, the company will provide further details on the investor and KOL event at a later date.

https://finance.yahoo.com/news/biomea-fusion-present-breaking-data-123000411.html

Elevance's upbeat profit forecast overshadowed by 2024 growth fears

 Elevance Health Inc's forecast raise and strong quarterly profit on Wednesday failed to ease investor concerns over regulatory hits to the company's government-backed insurance business, sending its shares down over 4%.

Elevance's medical costs in the first quarter beat analysts' expectations, mainly due to a delay in paying out claims, but were in-line with estimates after discounting the delay, analysts said.

The company's growth and ability to manage costs is already under the scanner as the health insurance industry faces lower government payouts for 2024 in the Medicare Advantage business.

Similar worries sent larger rival UnitedHealth's shares down nearly 3% on Friday despite the health insurance industry bellwether beating estimates for first-quarter profit.

"We suspect Elevance shares are declining on near-term headwinds that may emerge related to Medicaid redeterminations later this year and Medicare Advantage primarily in 2024," Morningstar analyst Julie Utterback said.

Medicaid memberships are expected to be hit from the removal of pandemic-related relief measures, as several members who had signed up under those provisions for the government-aided plans become ineligible beginning April 1.

Elevance's benefit expense ratio, a measure of the share of premiums paid for medical services, was 85.8% in the first quarter, compared with analysts' expectations of 85.98%, according to Refinitiv.

On an adjusted basis, the company now expects annual profit of more than $32.70 per share, compared with its previous forecast of over $32.60 per share.

Excluding items, Elevance earned $9.46 per share, above estimates of $9.26 per share.

https://news.yahoo.com/elevance-health-raises-annual-profit-103624944.html

Why Intuitive Surgical Stock Is Soaring

 

Intuitive's impressive Q1 results were driven by a surge in procedure volume for its da Vinci robotic surgical system.

Shares of Intuitive Surgical (ISRG 12.17%) were soaring 12.6% higher as of 10:59 a.m. ET on Wednesday. The big gain came after the robotic surgical systems leader announced its first-quarter results following the market close on Tuesday.

Intuitive Surgical reported Q1 revenue of $1.7 billion, up 14% year over year. The consensus estimate was for revenue of $1.6 billion.

The company posted Q1 earnings of $355 million, or $1 per diluted share, based on generally accepted accounting principles (GAAP). This result was down from GAAP earnings of $366 million, or $1 per diluted share, in the prior-year period.

Intuitive generated non-GAAP earnings in the first quarter of $437 million, or $1.23 per diluted share. This reflected solid improvement from non-GAAP earnings of $413 million, or $1.13 per diluted share, in the first quarter of 2022. It also topped the average analysts' earnings estimate of $1.20 per share.

Perhaps the most encouraging aspect of Intuitive Surgical's Q1 update is that the company delivered strong growth despite continuing to face two headwinds. First, COVID-19 caused procedure volumes in China to be lower in January. Second, the sustained strength of the U.S. dollar resulted in lower revenue growth. Intuitive said that Q1 sales increased 17% year over year on a constant-currency basis compared to the 14% increase reported.

This solid performance was driven primarily by strong procedure volume growth. Intuitive reported that da Vinci procedures soared around 26% year over year. CEO Gary Guthart noted the "positive surgical trends" and added that there is "continued interest in robotic-assisted surgery when compared with other surgical approaches."

While da Vinci is Intuitive's main growth engine, the company's Ion endoluminal robotic system could contribute more in the near future. Intuitive won European certification for Ion in March. It plans to focus first on the U.K. market while additional clinical data is collected to support reimbursement in other European countries.

https://www.fool.com/investing/2023/04/19/why-intuitive-surgical-stock-is-soaring-today/

Revive Update of Phase 3 Clinical Study for Bucillamine in Treatment of COVID-19

 Revive Therapeutics Ltd. (“Revive” or the “Company”) (OTCQB: RVVTF) (CSE: RVV) (FRANKFURT: 31R), a specialty life sciences company focused on the research and development of therapeutics for medical needs and rare disorders, announced today an update on the Company’s U.S. Food & Drug Administration (“FDA”) Phase 3 clinical trial (the “Study”) (NCT04504734) to evaluate the safety and efficacy of Bucillamine, an oral drug with anti-inflammatory and antiviral properties, in patients with mild to moderate COVID-19. Following the Type C meeting with the FDA, the Company has reviewed the current environment of new hospital admissions of patients with confirmed COVID-19 internationally and in the U.S., where it is steadily declining (Source: CDC), evaluated potential patient recruitment strategies, and discussed with potential pharmaceutical partners to pursue Bucillamine as a potential treatment for COVID-19.

After further regulatory discussions with various groups, the Company has now decided that it will have the Data Safety Monitoring Board (“DSMB”) review the Study’s Post-Dose selection data of approximately 500 subjects for efficacy. This will take place under the current Study’s protocol primary endpoint, the proportion of patients meeting a composite endpoint of hospitalization or death from time of first dose through Day 28 following randomization. The DSMB may then recommend continuing the Study if there is a trend toward achieving statistical significance, halting the Study early due to statistical significance likely not going to be met, or halting the Study early due to positive efficacy showing statistical significance. In the latter case, the Company would request a meeting with the FDA to determine the appropriate next steps toward obtaining potential regulatory approval. Should the DSMB recommend continuing the Study, the Company will then evaluate the current environment of COVID-19 and the likelihood of efficiently obtaining hospitalizations for the remainder of the Study and potentially bringing a pharmaceutical partner to support the continuation of the Study. Should the DSMB recommend not to pursue the Study due to statistical significance likely not going to be met, the Company will accept the DSMB decision and seek an evaluation of COVID-19 clinical symptoms data (i.e. cough, fever, heart rate, and oxygen saturation), which will support further discussions with the FDA and potential pharmaceutical partners to determine a suitable regulatory approval pathway for Bucillamine in the U.S. and internationally.

The Company is committed to advancing the clinical and commercial development of Bucillamine and plans to pursue the following activities:

1. Continue discussions with the FDA on a pathway for future potential regulatory approval under the Study’s objectives or clinical symptoms data;
   
2. Work with interested pharmaceutical partners to pursue potential international regulatory approvals and new clinical studies for Long COVID or COVID symptom-related conditions and various infectious, inflammatory and respiratory disorders; and
   
3. Develop reformulation strategies of Bucillamine to expand on its potential therapeutic utility targeting rare disorders that may come with regulatory incentives awarded by the FDA, such as orphan drug (i.e. ischemia-reperfusion injury, cystinuria), fast track, and breakthrough therapy designations.

https://www.globenewswire.com/news-release/2023/04/18/2649628/0/en/Revive-Therapeutics-Provides-Update-of-Phase-3-Clinical-Study-for-Bucillamine-in-the-Treatment-of-COVID-19.html

False Messaging on Vaccines Given to Pregnant Women

 The mRNA vaccines were released globally in early 2021 with the slogan ‘safe and effective.’ Unusually for a new class of medicine, they were soon recommended by public health authorities for pregnant women. 

By late 2021, working-age women, including those who were pregnant, were being thrown out of employment for not agreeing to be injected. Those who took the mRNA vaccines did so based on trust in health authorities – the assumption being that they would not have been approved if the evidence was not absolutely clear. The role of regulatory agencies was to protect the public and, therefore, if they were approved, the “vaccines” were safe.

Recently, a lengthy vaccine evaluation report sponsored by Pfizer and submitted to the Australian regulator, the Therapeutic Goods Administration (TGA) dated January 2021 was released under a Freedom of Information request. 

 The report contains significant new information that had been suppressed by the TGA and by Pfizer itself. Much of this relates directly to the issue of safety in pregnancy, and impacts on the fertility of women of child-bearing age. The whole report is important, but four key data points stand out;

• The rapid decline in antibody and T cells in monkeys following second dose, 
• Biodistribution studies (previously released in 2021 through an FOI request in Japan)
• Data on the impact of fertility outcomes for rats.
• Data on fetal abnormalities in rats.

We focus on the last three items as, for the first point, it is enough to quote the report itself “Antibodies and T cells in monkeys declined quickly over 5 weeks after the second dose of BNT162b2 (V9), raising concerns over long term immunity…”.

This point indicates that the regulators should have anticipated the rapid decline in efficacy and must have known at the outset that the initial two-dose “course” was unlikely to confer lasting immunity and would, therefore, require multiple repeat doses. This expectation of failure was recently highlighted by Dr Anthony Fauci, former director at the US NIH. 

The three remaining items should be a major cause for alarm with the pharmaceutical regulatory system. The first, as revealed in 2021, involved biodistribution studies of the lipid nanoparticle carrier in rats, using a luciferase enzyme to substitute for the mRNA vaccine. 

The study demonstrated that the vaccine will travel throughout the body after injection, and is found not only at the injection site, but in all organs tested, with high concentration in the ovaries, liver, adrenal glands, and spleen. Authorities who assured vaccinated people in early 2021 that the vaccine stays in the arm were, as we have known for two years, lying.

Lipid concentration per gram, recalculated as percentage of injection site.

ORGAN	28 HOURS µg lipid equiv/g	TOTAL	CONC VS INJECTION SITE
ADRENAL	18.21	164.9	11.04%
MARROW	3.77	164.9	2.29%
SITE	164.9	164.9	100.00%
LIVER	24.29	164.9	14.73%
OVARIES	12.26	164.9	7.43%
SPLEEN	23.35	164.9	14.16%

In terms of the impact on fertility and fetal abnormalities, the report includes a study of 44 rats and describes two main metrics, the pre-implantation loss rate and the number of abnormalities per fetus (also expressed per litter). In both cases the metrics were significantly higher for vaccinated rats than for unvaccinated rats.

Roughly speaking, the pre-implantation loss ratio compares the estimated number of fertilised ova and the ova implanted in the uterus. The table below is taken from the report itself and clearly shows the loss rate for vaccinated (BNT162b2) is more than double the unvaccinated control group.

In a case control study, a doubling of pregnancy loss in the intervention group would represent a serious safety signal. Rather than take this seriously, the authors of the report then compared the outcomes to historical data on other rat populations; 27 studies of 568 rats, and ignored the outcome because other populations had recorded higher overall losses; this range is shown in the right hand column as 2.6 percent to 13.8 percent. This analysis is alarming as remaining below the highest previously recorded pregnancy loss levels in populations elsewhere is not a safe outcome when the intervention is also associated with double the harm of the control group.

A similar pattern is observed for fetal malformations with higher abnormality rate in each of the 12 categories studied. Of the 11 categories where Pfizer confirmed the data is correct, there are only 2 total abnormalities in the control group, versus 28 with the mRNA vaccine (BNT162b2). In the category which Pfizer labeled as unreliable (supernumerary lumbar ribs), there were 3 abnormalities in the control group and 12 in the vaccinated group.

As with the increased pregnancy losses, Pfizer simply ignored the trend and compared the results with historical data from other rat populations. This is very significant as it is seen across every malformation category. The case control nature of the study design is again ignored, in order to apparently hide the negative outcomes demonstrated.

These data indicate that there is NO basis for saying the vaccine is safe in pregnancy. Concentration of LNPs in ovaries, a doubled pregnancy loss rate, and raised fetal abnormality rate across all measured categories indicates that designating a safe-in-pregnancy label (B1 category in Australia) was contrary to available evidence. The data implies that not only was the Government’s “safe and effective” sloganeering not accurate, it was totally misleading with respect to the safety data available.

Known unknowns and missing data: 

Despite the negative nature of these outcomes, the classification of this medicine as a vaccine appears to have precluded further animal trials. Historically, new medicines, especially in classes never used in humans before, would require a very rigorous assessment. Vaccines, however, have a lower burden of proof requirement than ordinary medicines. By classifying mRNA injections as “vaccines,” this ensured regulatory approval with significantly less stringent safety requirements, as the TGA itself notes. 

In fact, mRNA gene therapies function more like medicines than vaccines in that they modify the internal functioning of cells, rather than stimulating an immune response to presence of an antigen. Labelling these gene therapy products as vaccines means that, as far as we are aware, even today no genotoxicity or carcinogenicity studies have been carried out.

This report, which was only released after a FOI request, is extremely disturbing as it shows that authorities knew of major risks with mRNA Covid-19 vaccination while simultaneously assuring populations that it was safe. The fact that mainstream media has (as far as we are aware) completely ignored the newly released data should reinforce the need for caution when listening to the advice of public health messaging regarding Covid-19 vaccination.

Firstly, it is clear that regulators, drug companies and the government would have known that vaccine-induced immunity tails off very rapidly with this being observed in real world data with efficacy against infection falling to zero. Accordingly, the single point in time figures of 95 percent and 62 percent efficacy against cases quoted for Pfizer and ChAdOx1 (AstraZeneca) respectively meant almost nothing since a rapid decline was to be expected. 

Similarly, the concept of a two-dose “course” was inaccurate as endless boosters would likely have been required given the rapid decline in antibodies and T-cells observed in the monkeys.

Most importantly, the data does not in any way support the “safe” conclusion with respect to pregnancy; a conclusion of dangerous would be more accurate. The assurances of safety were, therefore, completely misleading given the data disclosures in the recent freedom of information release. 

Regulatory authorities knew that animal studies showed major red flags regarding both pregnancy loss and fetal abnormalities, consistent with the systemic distribution of the mRNA they had been hiding from the public. 

Even in March 2023, it is impossible to give these assurances, given the fact that important studies have not, to the best of our knowledge, been done. 

Pfizer elected not to follow up the vast majority of pregnancies in the original human trials, despite high miscarriage rates in the minority they did follow. Given all of the problems with efficacy and safety, the administration of these products to women of childbearing age, and administration to healthy pregnant women is high-risk and not justified. 

David Bell, Senior Scholar at Brownstone Institute, is a public health physician and biotech consultant in global health. He is a former medical officer and scientist at the World Health Organization (WHO), Programme Head for malaria and febrile diseases at the Foundation for Innovative New Diagnostics (FIND) in Geneva, Switzerland, and Director of Global Health Technologies at Intellectual Ventures Global Good Fund in Bellevue, WA

https://brownstone.org/articles/the-false-messaging-on-vaccines-given-to-pregnant-women/