Gilead's CAR-T therapy won a third adaptation; the Nobel Prize-winning founding company completed the first editing of bone marrow cells in CRISPR

▎74% of patients with WuXi AppTec's content team have sustained remission for more than 18 months.
Gilead's CAR-T therapy won the third indication.
Kite Pharma, a subsidiary of Gilead Sciences, recently announced that the U.
S.
FDA has accelerated its approval of CAR-T therapy.
Yescarta (axicabtagene ciloleucel) has extended indications for the treatment of adult patients with relapsed/refractory follicular lymphoma (FL).

They have received at least two systemic treatments.

The press release stated that this is the first CAR-T cell therapy approved for the treatment of patients with indolent follicular lymphoma.

Follicular lymphoma is the most common form of indolent lymphoma and the second most common type of lymphoma in the world.

It accounts for approximately 22% of all lymphomas diagnosed worldwide.

Currently, after two or more lines of treatment, treatment options for relapsed/refractory follicular lymphoma are limited.

Yescarta is the second CAR-T cell therapy approved by the FDA for the treatment of adult patients with relapsed/refractory large B-cell lymphoma.

It guides and activates T cells to kill cancerous B cells by targeting the CD19 antigen on the surface of B cells.

This approval is based on the results of a single-arm, open-label study called ZUMA-5.

The results of the trial showed that 91% of patients with relapsed/refractory follicular lymphoma (n=81) responded to Yescarta, and 74% of them were in continuous remission after receiving treatment for 18 months.

At a median follow-up time of 14.
5 months, the median remission time has not yet been reached. One-time medication is effective for one year, and the early clinical results of AIDS prevention therapy are positive.
Recently, Merck & Co.
(MSD) announced that its investigating nucleoside reverse transcriptase inhibitor (NRTTI) islatravir (also known as MK-8591) is in a phase 1 Positive results in clinical trials.

Three different doses of islatravir are administered in the form of a subcutaneous sustained-release implant (implant), which can maintain the drug concentration above the predetermined pharmacokinetic (PK) threshold for 12 weeks after implantation.

Islatravir at a dose of 56 mg is expected to keep the drug concentration above the threshold for more than a year.

Based on this positive result, Merck will launch a phase 2 clinical trial to further explore the potential of islatravir subcutaneous implants as a long-acting pre-exposure prophylaxis (PrEP) therapy.

It may provide up to 12 months of protection with just one dose.

With the emergence of "cocktail therapy", AIDS has changed from a disease-causing disease that has become a fascinating disease to a chronic disease that can be controlled by drugs.

But in some countries, the incidence of AIDS is still very high.

Pre-exposure prophylaxis is designed to provide preventive treatment to people who are at risk of HIV-1 infection and reduce their risk of HIV-1 infection.

However, current preventive therapies require high-risk groups to take drugs every day, and poor compliance with medications will increase their risk of infection.

Islatravir is an innovative NRTTI developed by Merck.
Preclinical studies have shown that it can inhibit the function of HIV reverse transcriptase through a variety of mechanisms.
Its mechanism of action is different from the currently approved anti-HIV therapies and traditional nucleoside reverse transcriptase inhibition.
Agents (NRTIs).

Merck is currently testing its efficacy as a single-agent PrEP therapy and in combination with other antiviral therapies in the treatment of HIV infection in a number of clinical trials.

▲The molecular structure of Islatravir (picture source: Edgar181, Public domain, via Wikimedia Commons) In this double-blind, placebo-controlled phase 1 clinical trial, 24 healthy participants implanted a plant containing different doses of islatravir in their upper arms.
Into the body, it can slowly release the drug in the body, so as to achieve the effect of maintaining the therapeutic concentration of the drug for a long time.

After 12 weeks of implantation, the implant was removed, and the participant then underwent an 8-week evaluation.

The test results showed that the three different doses of implants maintained the concentration of islatravir above the level of antiviral efficacy within 12 weeks.

The higher doses (52 mg and 56 mg) of islatravir were able to maintain the drug concentration above the threshold after the implant was removed, until the end of the study.

Based on the results of these trials and previous evaluations of islatravir implants, the researchers expect that this method of administration can maintain the drug concentration above the target PK threshold for at least one year.

Reduce the risk of hospitalization/death by 87%! Eli Lilly and Company's neutralizing antibody combination achieved good results in Phase 3 clinical trials.
Recently, Eli Lilly and Company announced that the latest results of phase 3 clinical trials showed that neutralizing antibodies bamlanivimab (LY-CoV555, 700 mg) and etesevimab The combination therapy (LY-CoV016, 1400 mg) can reduce the risk of hospitalization or death of early high-risk COVID-19 patients by 87%.

Previously, this neutralizing antibody combination has received an emergency use authorization (EUA) from the US FDA for the treatment of mild and moderate patients over 12 years of age who progress to severe COVID-19 or are at high risk of hospitalization.

Bamlanivimab is a neutralizing antibody jointly developed by Eli Lilly and AbCellera, and has been granted emergency use authorization (EUA) by the US FDA.

The results of phase 3 clinical trials that have been released show that it can be used as a preventive treatment to reduce the risk of illness for the elderly living in nursing homes by 80%.

Etesevimab (LY-CoV016, also known as JS016) was originally jointly developed by Junshi Biology and the Institute of Microbiology, Chinese Academy of Sciences.
Last year, Eli Lilly obtained a license from Junshi Biology to lead clinical development in global regions outside of Greater China.

Both antibodies target the Spike Protein Receptor Binding Domain (RBD), but target different epitopes of RBD, so the combination therapy may produce better therapeutic effects.

▲Bamlanivimab and etesevimab antibody profile (picture source: Eli Lilly's official website) The data released today comes from 769 mild and moderate COVID-19 patients over 12 years old who are at high risk of progressing to severe COVID-19 or hospitalization Type of patient.

Of these patients, 511 received the neutralizing antibody combination therapy and 258 received placebo treatment.

In the neutralizing antibody group, there were a total of 4 hospitalizations or deaths, compared with 15 cases in the control group.

It is calculated that neutralizing antibody therapy can reduce the risk of hospitalization or death by 87%.

Previously, the neutralizing antibody combination therapy at a dose of 2800 mg reduced the risk of hospitalization or death by 70% in another patient cohort in this phase 3 clinical trial.

In this patient cohort, there were a total of 4 deaths related to COVID-19, all of which occurred in the placebo group.

So far, in the two patient cohorts evaluated in phase 3 clinical trials, a total of 13 COVID-19-related deaths have been found, and none of them appeared in the neutralizing antibody combination therapy group.

▲Data on different doses of Bamlanivimab and etesevimab antibody combination therapy to reduce the risk of hospitalization in patients (picture source: reference [3]) for the treatment of advanced renal cell carcinoma, FDA approved a new generation of VEGF receptor inhibitor AVEO Oncology recently announced that the US FDA approved Fotovda (Tivozanib) is marketed for the treatment of adult patients with relapsed/refractory advanced renal cell carcinoma (RCC), who have received more than two pre-systemic therapies.

Fotivda is a new generation of vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor (TKI).

RCC is the most common type of kidney cancer, and it is more common in the elderly.

Patients with early RCC usually do not show symptoms, but as the disease worsens, symptoms include hematuria, low back pain, weight loss, and anemia.

At present, there are a variety of treatment options for RCC patients, including surgery, targeted therapy, and immunotherapy.
However, when the cancer becomes resistant to existing therapies, the patient's options are very limited.

Fotivda is an oral VEGF receptor tyrosine kinase inhibitor (TKI).
It was originally discovered by Kyowa Hakko Kirin, and was approved in the European Union for the treatment of adult patients with advanced RCC.

It can selectively and strongly inhibit all three VEGF receptors and has a long half-life.
It can effectively block the VEGF signaling pathway while minimizing off-target side effects.

In preclinical studies, it can also significantly reduce the production of regulatory T cells.

▲Fotivda molecular structure (picture source: Edgar181, Public domain, via Wikimedia Commons) This approval is based on the positive results of the pivotal phase 3 clinical study TIVO-3.

In this trial, patients with advanced RCC received Fotivda or active control treatment, and the primary efficacy endpoint was progression-free survival (PFS).

The test results showed that the PFS of the Fotivda group was 5.
6 months, which was better than the 3.
9 months of the active control group (HR=0.
73, 95% CI: 0.
56, 0.
95; p=0.
016).

In terms of objective response rate (ORR), Fotivda reached 18%, and the value of the active control group was 8%.

KRAS inhibitors add another force.
Eli Lilly’s innovative therapy is about to start clinical trials.
KRAS gene is one of the most frequently mutated oncogenes in human cancers.
In addition to directly promoting the proliferation and survival of tumor cells, its mutations can also affect tumor cells.
The environment has an impact.

Because its surface lacks a "pocket" that can bind to small molecule drugs, KRAS protein is also a famous "undrugable" target in history.

However, the development of drugs for KRAS mutants has achieved breakthroughs in recent years.
Amgen and Mirati Therapeutics' small molecule inhibitors for KRAS G12C mutants have entered a critical clinical development stage.
Among them, Amgen's KRAS G12C inhibitors have been obtained.
The FDA’s priority review qualification is expected to be approved this year.

A few days ago, Eli Lilly and Company announced that it will announce the preclinical research results of its next-generation KRAS G12C specific inhibitor LY3537982 at the AACR annual meeting in April this year.

Based on the positive preclinical results, the company plans to launch a phase 1 clinical trial this year to test the safety and potential efficacy of this candidate drug.

The abstract released by AACR showed that this specific KRAS G12C inhibitor showed good activity in in vitro experiments.

The activation of KRAS needs to be combined with GTP.
KRAS G12C inhibitors bind KRAS G12C mutants to lock KRAS in a state of binding to GDP, thereby inhibiting KRAS signal transduction.

In lung cancer cell lines carrying the KARS G12C variant, the IC50 of LY3537982 inhibiting the binding of KRAS to GTP reached 3.
35 nM.

In a variety of mouse tumor models containing KRAS G12C gene mutations, LY3537982 can significantly inhibit tumor proliferation or lead to complete tumor regression.

Preclinical studies also found that certain targeted therapies combined with LY3537982 may produce better anti-cancer effects, including the specific AurA inhibitor LY3295668 and the EGFR inhibitor cetuximab.

Researchers have shown that this potent KRAS G12C inhibitor is expected to nearly completely inhibit the activation of KRAS protein, which may provide the greatest clinical benefit for patients with KRAS G12C gene mutations.

The Nobel laureate’s creation of a company has achieved another breakthrough.
It is the first time to complete CRISPR in vivo editing of bone marrow cells.
Intellia Therapeutics is a biotechnology company co-founded by Dr.
Jennifer Doudna, the Nobel Prize winner in chemistry in 2020.
It is committed to using CRISPR gene editing technology in vivo and in vitro.
Perform gene editing to develop innovative therapies.

In November last year, the company's research gene editing therapy NTLA-2001 completed the first patient administration in a phase 1 clinical trial, achieving the first systemic administration of gene editing in the human body based on CRISPR/Cas9 technology.

A few days ago, the company announced that it has completed a proof-of-concept of in vivo gene editing of bone marrow and hematopoietic stem cells in preclinical studies.

The press release pointed out that this is the first time the company has demonstrated that using a non-viral delivery platform, systemic drug delivery can be used to complete in vivo gene editing of tissues other than the liver.

For the development of therapies for the treatment of inherited blood diseases such as sickle cell anemia (SCD), this breakthrough is expected to overcome the operational complexity and safety risks associated with in vitro gene editing.

Gene editing therapy has shown the potential for functional cure in clinical trials for the treatment of β-thalassemia (TDT) and SCD patients.

However, this kind of gene editing therapy requires collecting hematopoietic stem cells from the patient, performing gene editing in vitro, and then infusing it back into the patient.

The entire therapy manufacturing process is complicated, and before receiving treatment, patients need to receive drug treatment to remove existing stem cells in the bone marrow to provide growth space for the imported cells.

This brings immunosuppression, infection, and potential cancer risks associated with chemotherapy drugs.

The in vivo gene editing technology developed by Intellia aims to deliver the gene editing system directly to the bone marrow through lipid nanoparticles (LNPs) to edit bone marrow cells and hematopoietic stem cells, thereby eliminating the complex process of editing cells in vitro and removing There are steps for bone marrow stem cells.

However, the problem that this strategy needs to solve is that liposomes are usually first absorbed by the liver.
If you want to target and edit stem cells in the bone marrow, you need to design bone marrow-targeted LNPs.

Image source: Reference materials[7] In a recent report, the bone marrow-directed LNPs designed by Intellia can successfully edit bone marrow and hematopoietic stem cells and progenitor cells in vivo in a mouse model, and the level of gene editing is expected to be A functional cure effect is achieved in SCD patients.

▲The CRISPR system carried by bone marrow-oriented lipid nanoparticles has successfully performed gene editing on bone marrow and hematopoietic stem cells/progenitor cells (picture source: reference [7]).
The difference from viral vector-based gene editing therapy is that the LNP delivery platform does not It will stimulate the immune response of the immune system, so it can be administered repeatedly to further enhance the effect of gene editing.

In the report, the researchers also showed that the use of LNP multiple delivery gene editing system can increase the editing ratio of bone marrow and hematopoietic stem cells in mice.

▲Multi-dose treatment increases the editing ratio of bone marrow and hematopoietic stem cells (picture source: reference [7]) Note: This article aims to introduce medical and health research, not a treatment plan recommendation.

If you need guidance on treatment plans, please go to a regular hospital for treatment.

Reference: [1] US FDA Approves Yescarta® for Relapsed or Refractory Follicular Lymphoma After Two or More Lines of Systemic Therapy.
Retrieved March 6, 2021, from https:// [2] Merck Presents Results from Phase 1 Trial Evaluating Investigational Islatravir Subdermal Implant for the Prevention of HIV-1 Infection at CROI 2021.
Retrieved March 8, 2021, from https:// en[3] Lilly's bamlanivimab and etesevimab together reduced hospitalizations and death in Phase 3 trial for early COVID-19.
Retrieved March 10, 2021, from https:// etesevimab-together-reduced-hospitalizations-and-death-in-phase-3-trial-for-early-covid-19-301243984.
html[4] AVEO Oncology Announces USFDA Approval of FOTIVDA® (tivozanib) for the Treatment of Adult Patients with Relapsed or Refractory Advanced Renal Cell Carcinoma.
Retrieved March 10, 2021, from https:// Lilly rejoins KRAS race with swipe at Amgen and Mirati, plans 2021 clinical trial.
Retrieved March 11, 2021 from https:// mirati-plans-2021-clinical-trial[6] 1259-Preclinical characterization of LY3537982, a novel, highly selective and potent KRAS-G12C inhibitor.
Retrieved March 11, 2021, from https:// #!/9325/presentation/2344[7] In Vivo Gene Editing of Hematopoietic Stem and Progenitor Cells.
Retrieved March 11, 2021, from https://3o5c4w3neipl16yvhj3nfqam-wpengine.
netdna-ssl.
com/wp-content/uploads/Keystone_2021_BoneMarrow_10Mar2021.
pdf[8] Intellia Therapeutics Presents Preclinical Proof of Concept for CRISPR-based In Vivo Editing of Bone Marrow at Keystone eSymposium.
Retrieved March 11, 2021, from https://ir.
intelliatx.
com/news-releases/news-release-details/intellia-therapeutics-presents-preclinical-proof-concept-crispr