How to develop biosimilars under GMP

The FDA's decision is of special significance because health insurers have been delaying reimbursement payments for lecanemab until it receives full FDA approval for its treatment, which costs $26,500 per year.

Lecanemab was published in the New England Journal of Medicine (NEJM) on November 29, 2022. Results from a Phase III clinical trial involving nearly 1,800 patients with early-stage Alzheimer's disease showed that the drug slowed cognitive decline in Alzheimer's disease patients by 27%.

Lecanemab is a humanized IgG1 monoclonal antibody that works by binding to beta-amyloid (A?).

In the clinical trial, patients with early Alzheimer's disease received intravenous lecanemab or a placebo every two weeks for 18 months. Researchers used an 18-point scale to measure their cognitive performance. The results showed that lecanemab delayed the patients' deterioration by about five months. Additionally, patients who received lecanemab were 31% less likely to progress to the next stage of the disease during the study period.

However, adverse reactions in the clinical trial results sparked controversy. 7.3% of patients treated with the drug experienced brain hemorrhage (compared to 9% in the placebo control group), and 12.6% experienced brain swelling (compared to 1.7% in the placebo control group).

Alzheimer's disease experts remain divided on the impact of these changes in the drug on patients and families. Dr. Ron Petersen, a specialist at Mayo Medical Center, believes that the drug's effect is modest but clinically meaningful. Even if it only delays disease progression for a few months, it could provide Alzheimer's patients with more time to live and work independently.

Maria Carrillo, chief scientist at the Alzheimer's Association, stated that this clinical trial is important because it demonstrates that targeting amyloid with drugs can slow the progression of Alzheimer's disease. Delaying cognitive decline in the early stages of Alzheimer's disease has significant implications, allowing patients to spend more time with loved ones, enjoy family life, travel, take vacations, and fulfill their bucket lists.

Eisai stated that drugs targeting A? can cause side effects, including brain swelling and brain bleeding, and lecanemab is no exception. However, most patients experience mild or no symptoms.

According to published reports, three Alzheimer's disease patients died during clinical studies of the drug, two of them from strokes caused by brain hemorrhages. Eisai mentioned that the two deaths were due to other health problems while the patients were taking blood-thinning drugs, so these deaths cannot be attributed to the Alzheimer's disease drug.

Professor Robert Alexander from the University of Arizona, chairman of the FDA Peripheral and Central Nervous System Drugs Advisory Committee, commented that based on the results of clinical trials, lecanemab has side effects, but the monitorable nature of these side effects and the benefits to patients are evident.

This research takes the pursuit of immortality a step farther. The study found that using Alpelisib, a cancer drug, as a food supplement, can increase the average longevity of healthy mice by 10% starting in middle age, and behave better in old age group.

Alpelisib, an oral small molecule alpha-specific PI3K inhibitor developed by Novartis, was approved for marketing by the FDA in 2019 in combination with Fulvestrant for the treatment of patients with HR+/HER2- advanced or metastatic breast cancer carrying a mutation in the PIK3CA gene.

Middle-aged healthy mice were fed either a control diet or the same food with the Alpelisib drug added in this investigation. The findings revealed that mice fed an Alpelisib-containing diet not only survived longer, but also exhibited evidence of improved health in old age, such as improved coordination and strength.

Aging is not only about longevity, but also about quality of life, the team said. And this study shows that Alpelisib treatment not only extended the life span of healthy mice, but they also exhibited many signs of healthy aging. The research team is learning more about how these effects occur.

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Professor Peter Shepherd, the author of the paper, said, "Alpelisib targets an enzyme called PI3K and we have been working on developing drugs that target PI3K for more than 20 years since studies have revealed that the PI3K pathway is over-activated in many malignancies. It is exciting to see the use of PI3K inhibitors outside of cancer, since this shows novel processes that contribute to age-related disorders, demonstrating the worth of long-term investment in this science."

According to Associate Professor Troy Merry, the paper's corresponding author, it is not recommended that people take this drug for a long time to extend their life because it has some side effects as an anti-cancer drug, such as possibly causing high blood sugar, lung problems, allergic reactions, skin problems, and diarrhea. In addition, various negative effects were observed in this mouse trial, such as potentially creating reduced bone mass in mice. However, this research highlights essential aging pathways and will aid in the development of methods to prolong and maintain healthy longevity. This study also shows some potential applications for short-term Alpelisib treatment of specific metabolic health issues, which the research team is now investigating.

Targeted BsAbs for myocardial infarction therapy

On October 1 of this year, Molnupiravir presented promising data in Phase III clinical interim analysis, resulting in an early termination and an application to the U.S. Food and Drug Administration (FDA) for an Emergency Use Authorization (EUA). This UK approval is also based on the results of the interim analysis of the Phase III MOVe-OUT clinical trial.

Molnupiravir (MK-4482/EIDD-2801) is a nucleoside analog discovered by DRIVE, a non-profit organization affiliated with Emory University, which inhibits SARS-CoV-2 replication 3-10 times more actively than raltegravir and has shown activity in multiple preclinical SARS-CoV-2 prophylactic, therapeutic, and prophylactic transmission models. Merck and Ridgeback Biotherapeutics co-develop Molnupiravir, with Ridgeback receiving an initial payment from Merck and subsequent mileage payments dependent on clinical development and registration progress.

This trial was supposed to enroll 1,550 participants, but due to an early termination, only 775 have been enrolled so far.

Patients requesting inclusion had to meet all three of the following requirements at the same time.
* COVID-19 symptoms range from mild to moderate.
* At least one risk factor for serious disease (e.g., obesity, age over 60 years, diabetes, and heart disease).
* At the time of randomization, no more than 5 days had passed since the onset of symptoms.

The final patients recruited were composed of 55% Latin Americans, 23% Europeans, and 15% Africans, with about 80% infected with mutant Delta, Gamma, and Mu strains.

The primary indicator in the trial was the percentage of patients who were hospitalized or died of illness within 29 days of randomization to the group, and it was discovered that 7.3% (28/385) and 14.1% (53/377) were seriously ill or died in the Molnupiravir group, respectively. In this trial, eight patient died, but they were all in the control group. That is, Molnupiravir lowered the chances of progressing to severe disease or death by half and reduced the fatality rate to 0%.

The safety of Molnupiravir was also confirmed: for the adverse events, 35% and 40% in the Molnupiravir and control groups were observed, respectively, and for the adverse events related to drug, 12% and 11%, respectively, which were not statistically different. The percentage of discontinuation of treatment due to adverse effects was 1.3% and 3.4%, which was significantly lower in the Molnupiravir group.

What impact will Molnupiravir's approval have on the UK epidemic?

The advantages of Molnupiravir are outstanding. Firstly, its efficacy greatly reduces the chance of mild and moderate COVID-19 patients developing severe disease, which can largely reduce the chance of hospitalization of COVID-19 patients in the UK and effectively alleviate the crowding of medical resources.

Second, the price differential between an oral drug and an intravenous injection is significant, and Molnupiravir, as the first oral COVID-19 drug, may surely save the government a significant amount of medical expenditure. Simultaneously, Molnupiravir is effective against variant strains such as Delta, Gamma, and Mu, which can help limit the threat of SARS-CoV-2 variants.

However, Molnupiravir merely reduces the risk of severe disease and does not prevent infection, according to phase III clinical trials.

In any case, the fact that Molnupiravir was approved in the UK this time demonstrates that its efficacy and safety have been acknowledged. This is unquestionably a boon for the globe, particularly for those patients who may develop severe disease.

Transmission of SARS-CoV-2 in humans occurs through direct contact, respiratory droplets, contaminated objects and aerosols, with a full genome length of approximately 29.8 kb and several open reading frames (ORFs). The first ORF (ORF1a/b) encodes a polyprotein (nsp1-nsp16) required for viral replication and transcription, and the remaining 13 ORFs encode auxiliary and structural proteins, including spines (S), membranes (M), envelopes (E), and nucleocapsids (N). Animal models play a crucial role in SARS-CoV-2 mechanism and therapeutics studies.

Phenobarbital-induced liver microsomes for drug metabolism

Clinical features of COVID-19

1.General clinical symptoms

Pneumonia and other concomitant symptoms are the typical presentation of patients with SARS-CoV-2 infection. Fever (more than 90%) and cough (more than 80%) were the most prevalent symptoms. Various viral variations result in varied clinical signs, different morbidity, and different mortality in particular subpopulations.

2.Occurrence of infection in different populations

Acute respiratory distress syndrome, hospitalization, and mortality were more likely to result from severe or critical illnesses in elderly people with underlying chronic conditions. Fever (7/9), cough (4/9), myalgia (3/9), sore throat (2/9), diarrhea (1/9), and respiratory distress (1/9) are symptoms that pregnant women with SARS-CoV-2 infection present with. There are gender disparities in the severity of COVID-19, and childhood infections make up about 15% of all cases. Clinical manifestations of COVID-19 include skin lesions as well as respiratory, gastrointestinal, and neurological problems. It seems that males are more likely than females to have COVID-19 infection.

Receptors and cellular proteases mediating SARS-COV-2 infection

1.Classical receptors and new candidate receptors

ACE2 is the most widely recognized receptor for SARS-CoV-2. CD147-prickle protein interaction is a pathway for SARS-CoV-2 infection of host cells. ASGR1 mediates the internalization of galactose-terminated glycoproteins into hepatocytes and their degradation in lysosomes. Genomic receptor profiling identified ASGR1 and KREMEN1 as possible alternative functional receptors for SARS-CoV-2 entry into cells. SARS-CoV-2 infection promotes liver injury through pathways that may be influenced by previous pathological states and hepatic expression of NRP1. DPP4, AGTR2, ANPEP, and ENPEP are candidate receptors for SARS-CoV-2 infection.

2.Proteases mediating the entry of SARS-CoV-2 virus

A crucial part of SARS-CoV-2 infection and cell invasion is played by TMPRSS2. Key proteases enabling SARS-CoV-2 entrance into HEK 293/hACE2 cells are histone proteases B and L. The ability of the endogenous serine protease furin to cleave S proteins increases SARS-CoV-2 binding affinity for ACE2 receptors. Serine endopeptidase trypsin may be one of the proteases that contribute to SARS-CoV-2 entry. Other common host factors such as CSNK2B, GDI2, SLC35B2, DDX51, VPS26A, ARPP-19, C1QTNF7, ALG6, LIMA1, COG3, COG8, BCOR, LRRN2, and TLR9 may also regulate SARS-CoV-2 infection.

COVID-19 animal model

1.NHP

Non-human primates(NHPs) share significant similarities with humans in terms of physiological characteristics and immune regulation and have been intensively utilized to develop COVID-19 disease models. Rhesus monkeysare the most commonly used model of COVID-19 disease, but NHPs are facing great demand and soaring costs, so it may be necessary to find alternative models.

2.Mouse model

* Stably inherited transgenic mouse model.

Stably inherited transgenic mouse models expressing hACE2 resulted in SARS-CoV-2 susceptibility and could be used for preclinical evaluation of vaccines and drugs. Impaired lung function was observed in certain HFH4-hACE2 and K18-hACE2 mouse models of infection, with more efficient viral replication and severe disease manifestations in older mice.

Differences in hACE2 expression patterns in SARS-CoV-2 mouse models with different SARS-CoV-2 strains and different routes of infection and viral doses lead to different clinical manifestations and pathological changes.

* Mouse models of sensitization by Ad5-hACE2 or AAV-hACE2 transduction

Mice transduced in the adeno-trachea using an adeno-associated vector expressing hACE2 or adenovirus 5 (AAV-hACE2, Ad5-hACE2) resulted in hACE2 expression in lung tissue, allowing viral entry and infection.

* A model based on mouse-adapted SARS-CoV-2 strains

Intranasal inoculation of young mice with lung homogenates after SARS-CoV-2 infection of BALB/c mice produces mouse-adapted virus strain WBP-1. WBP-1 exhibits higher infectivity in BALB/c. Accumulation of mutations by successive passages and precise reverse genetic techniques allow the establishment of mouse-adapted strains.

* Humanized mouse models established with transplanted human tissue or cells

The SCID-hu lung mouse model and the recently established mouse model co-transplanted with human fetal lung tissue and myeloid-enhanced human immune system.

3.Syrian hamster model

Hamsters infected with SARS-CoV-2 develop respiratory and pulmonary disease and long-term damage to other physiological systems, and viral loads can be detected in the respiratory tract. Close contact transmission models have also been tested in hamsters, indicating that co-housing contact with hamsters carrying SARS-CoV-2 is an effective way to transmit the disease.

4.Ferret and mink models

Ferrets and mink, both members of the ferret family, are highly susceptible to several human respiratory viruses. After infection with SARS-CoV-2, ferrets exhibit common clinical signs and pathological examinations show varying degrees of lung damage. The prominent use of ferrets and mink is for transmission studies.

5.Poultry and livestock

Cats, dogs, chickens, pigs, and ducks can undergo SARS-CoV-2 infection but do not exhibit clinical signs, suggesting that an in vivomodel may not be appropriate. Infection of sheep supports only limited viral replication, which can occur via respiratory droplets or aerosols.

Liver-derived genomic DNA from cynomolgus monkeys is prized for its utility in:
* Toxicology and Pharmacokinetics: Preclinical studies rely on NHP models to evaluate drug metabolism, toxicity, and off-target effects, as their liver enzymes and genetic pathways closely mirror humans.
* Gene Editing and CRISPR Research: High-purity DNA supports functional genomics, enabling researchers to identify gene-disease associations or validate therapeutic targets.
* Immunotherapy Development: With the rise of antibody-drug conjugates (ADCs) and cell therapies, NHP DNA aids in assessing immune responses and optimizing biologics.

Industry Spotlight: Innovations in ADC Technology
A recent breakthrough in ADC design involves branched linkers, which improve drug stability and reduce off-target toxicity. Traditional ADCs, like the HER2-targeting T-DM1, faced limitations due to systemic side effects in clinical trials. However, novel linker technologiessuch as those incorporating branched structuresenhance tumor-specific payload delivery, as seen in next-generation ADCs currently under development.

This innovation aligns with the growing demand for precision medicine. For example, biotech companies are now leveraging NHP-derived genomic data to refine ADC pharmacokinetics (PK) and predict human responses more accurately.

The Role of NHPs in Modern Drug Discovery
Cynomolgus monkeys remain a gold standard for translational research. Their genomic DNA is particularly valuable for:
* Biomarker Discovery: Identifying genetic variants linked to disease susceptibility or drug resistance.
* Regulatory Compliance: Regulatory agencies like the FDA often require NHP data to approve first-in-human trials, emphasizing the need for reliable genomic resources.

A biotechnology company recently highlighted that over 80% of late-stage ADC candidates now incorporate NHP-derived data during preclinical phases, underscoring the material's critical role.

Ethical and Sustainable Practices
As the industry evolves, ethical sourcing of NHP biologicals has gained prominence. Organizations are adopting strict guidelines to ensure humane treatment and environmental sustainability, which also enhances data reproducibility.

Looking Ahead
The integration of multi-omics approaches (genomics, proteomics, and metabolomics) with NHP models is poised to accelerate biomarker discovery. Meanwhile, advances in synthetic biology may complementbut not yet replacethe need for primate-derived DNA in complex studies.

In summary, cynomolgus monkey liver genomic DNA remains a vital tool for bridging the gap between lab research and clinical success. As the biopharma industry prioritizes precision and safety, this resource will continue to drive innovations in oncology, immunology, and beyond.

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