​"First-in-class" peptide-conjugated drug obtained accelerated FDA approval; Eli Lilly's innovative diabetes treatment reached phase 3 clinical endpoint

▎The content team editor of WuXi AppTec has secured a breakthrough head and neck cancer therapy for approximately US$1 billion.
Merck, Germany has reached a licensing agreement.
Recently, Merck KGaA of Germany announced that it has reached a global licensing agreement with Debiopharm to develop cell apoptosis.
Xevinapant (Debio1143), a highly effective oral antagonist of Inhibitor of Apoptosis (IAP).

Xevinapant is a potential "first-in-class" drug.
It has been granted a breakthrough therapy designation by the FDA.
It is currently in phase 3 clinical trials in combination with platinum-containing chemotherapy and radiotherapy for the treatment of initially treated high-risk locally advanced drugs.
Squamous cell carcinoma of the head and neck.

Globally, head and neck cancer is the sixth most common type of cancer, with more than 650,000 newly diagnosed cases each year, and more than 330,000 patients die as a result.

Locally advanced squamous cell carcinoma of the head and neck is a highly disabling disease.
As the disease progresses, it may cause breathing, swallowing and speech disorders.

Despite the use of standard chemoradiation therapy, at least 40% to 60% of patients will have local or distant recurrence, so it is very important to find new treatments.

Xevinapant is a potent oral antagonist of potential "first-in-class" apoptosis protein inhibitors.

In preclinical studies, xevinapant restored the sensitivity of cancer cells to apoptosis, thereby depriving them of a major drug resistance mechanism.

▲The molecular structure of Xevinapant (picture source: PubChem) The results of a randomized double-blind phase 2 clinical trial that have been conducted show that adding xevinapant to standard care can significantly improve the local control rate of the patient's disease after 18 months.

When the follow-up time was 2 years, compared with standard care, the addition of xevinapant reduced the risk of disease progression and death by 63% (HR=0.
37, 95% CI: 0.
18, 0.
76; p=0.
0069).

At a follow-up of 3 years, xevinapant reduced the risk of death by 51%.

According to the agreement, Germany's Merck obtains the development and promotion rights of xevinapant on a global scale.

It will jointly conduct a registered Phase 3 clinical study with Debiopharm.

Debiopharm will receive an advance payment of 188 million euros and a milestone payment of up to 710 million euros.

The "first-in-class" peptide-conjugated drug has been approved by the FDA for the treatment of multiple myeloma.
Oncopeptides announced that the US FDA has accelerated the approval of Pepaxto (melphalan flufenamide, also known as melflufen) for the market, which is used in combination with dexamethasone.
For the treatment of adult patients with relapsed/refractory multiple myeloma (MM).

These patients have received at least four previous therapies, and the disease is resistant to at least one proteasome inhibitor, immunomodulator, and monoclonal antibody targeting CD38.

The press release states that Pepaxto is the first peptide drug conjugate approved by the FDA.

MM is a malignant blood cancer caused by abnormal proliferation of plasma cells in the bone marrow.

Cancerous plasma cells can affect the production of normal blood cells, leading to decreased blood cell index, bone damage and kidney damage.

Although in the past ten years, the emergence of innovative therapies has significantly revolutionized the treatment of MM.

However, many patients with MM will still relapse and develop resistance to existing therapies.
Therefore, these patients with relapsed/refractory MM still need new treatment options.

Pepaxto is a "first-in-class" peptide-conjugated drug that couples alkylating agents with peptides that target aminopeptidase.

Pepaxto can be quickly taken up by MM cells due to its lipophilicity.
In the cell, it will be quickly hydrolyzed by peptidase, thereby releasing the hydrophilic alkylating agent.

Aminopeptidase is overexpressed in tumor cells, especially in advanced cancers or tumors with high mutation complexes.

In in vitro experiments, Pepaxto can increase the concentration of the alkylating agent in the cell, and its ability to kill MM cells is 50 times higher than that of the alkylating agent it carries.

▲The molecular structure of Pepaxto (picture source: Ed (Edgar181) / Public domain) This approval is based on the results of the pivotal Phase 2 clinical trial HORIZON.

In this clinical trial, 157 patients with relapsed/refractory MM received a combination therapy consisting of Pepaxto and dexamethasone.

The test results showed that the combination therapy reached an overall remission rate of 23.
7%, and the median duration of remission was 4.
2 months.

Yang Luhan’s co-founding company receives US$125 million in assistance.
A few days ago, eGenesis, which is committed to developing organs, tissues and cells compatible with humans, announced that it has completed a US$125 million Series C financing.

The funds obtained will be used to promote the company's main R&D project in kidney and islet cell transplantation into human proof-of-concept research.

In addition, the funds will be used for the continuous development of the company's proprietary gene editing platform and the expansion of GMP production scale.

Currently, the demand for life-saving organs far exceeds the available supply.

In the United States alone, more than 110,000 people are included in the national transplant list.

Due to the lack of transplantable organs, 20 people die every day.

In China, there are 300,000 patients who are suitable for organ transplantation treatment every year, but only more than 10,000 people can be treated by organ transplantation.

eGenesis was co-founded by Professor George Church of the Massachusetts Institute of Technology (MIT) and Dr.
Luhan Yang, aiming to genetically edit pig organs to meet the requirements for safe and successful transplantation into the human body. The pig’s heart, kidney, liver and other organs are similar in size to human organs, and their histological and physiological characteristics are also similar.
Therefore, many scientists believe that pigs are the most suitable animal for providing heterogeneous organs.

However, to transplant pig organs, at least two important obstacles need to be resolved.

On the one hand, the body’s immune system rejects other organs, and the interaction between human blood and pig tissues can cause abnormal blood clotting and bleeding.

On the other hand, the pig’s genome contains viral DNA sequences, which are called porcine endogenous retroviruses (PERVs), which produce potentially infectious virus particles and are risky to human health.

eGenesis is committed to solving the above problems and developing organs, tissues and cells compatible with humans.

In 2019, more than a dozen piglets 3.
0 that have undergone CRISPR gene editing have successfully come out.
They are the animals with the largest number of gene editing so far.

According to various tests conducted by researchers on cells, the organ tissue characteristics of these piglets can meet the requirements for safe and successful transplantation into humans.

▲eGenesis's R&D pipeline (picture source: eGenesis's official website) successfully promoted hair regrowth! Eli Lilly and Company's JAK inhibitor reaches phase 3 clinical endpoint Eli Lilly and Company and Incyte have jointly announced that the oral JAK inhibitor baricitinib has reached the primary endpoint in a phase 3 clinical trial for the treatment of adult patients with severe alopecia areata (alopecia areata).

After 36 weeks of treatment, compared with the placebo group, the patient's hair regrowth was significantly improved.

The press release states that baricitinib is the first JAK inhibitor to promote hair regrowth in a phase 3 clinical trial for the treatment of alopecia areata.

Alopecia areata is the second highest incidence of hair loss in the world.
There are approximately 147 million patients with alopecia areata in the world, and there are about 4 million patients in China.

It is an autoimmune disease in which the immune system attacks the hair follicles, causing partial or complete hair loss on the scalp, face or other parts of the body.

Alopecia areata symptoms often occur for the first time in childhood, and people of any age, gender, and race may suffer from alopecia areata.

Currently, it has no FDA-approved therapy.

Baricitinib is an oral JAK inhibitor.

The JAK family is a class of cytoplasmic tyrosine kinases, including four subtypes: JAK1, JAK2, JAK3, and TYK2.

They play an important role in mediating the signal transduction of a variety of cytokine receptors.
The signal pathway mediated by JAK is related to cell proliferation, differentiation, apoptosis and inflammation.

Baricitinib has been approved in more than 70 countries in the world for the treatment of moderate to severe active rheumatoid arthritis, under the trade name Olumiant.

It has been granted a breakthrough therapy designation by the FDA for the treatment of alopecia areata.

In this randomized, double-blind, placebo-controlled Phase 3 clinical study called BRAVE-AA2, 546 patients with severe alopecia areata (more than 50% of their hair loss) received treatment with baricitinib or placebo.

It is worth mentioning that this trial included a broad patient population from many countries in the world, including China, South Korea, Japan, Brazil, Australia, Argentina, and the United States.

The results of the trial showed that the two different doses of baricitinib reached the primary endpoint of the trial at 36 weeks, and the safety profile was consistent with the safety profile in the treatment of patients with rheumatoid arthritis and atopic dermatitis.

Detailed results will be announced at a future medical conference and will be published in a peer-reviewed journal later this year.

"For patients with alopecia areata, this is not just a disease that affects appearance, but a serious autoimmune disease that can have a significant psychological impact.
What
they lose is far more than just hair.

" said Dr.
Lotus Mallbris, vice president of immunology development at Eli Lilly.
"We look forward to sharing all the data from the clinical development of baricitinib, which is expected to become the first approved therapy for alopecia areata. "Baricitinib is currently in another phase 3 clinical trial for the treatment of patients with alopecia areata, and the results are expected to be announced in the first half of this year.

Image source: 123RF In the treatment of alopecia areata, JAK inhibitors are the first treatment that is expected to achieve a breakthrough.

At present, apart from ceremony In addition to the baricitinib developed in cooperation with Incyte, many JAK inhibitors are also used in clinical trials to treat alopecia areata.

Among them, ritlecitinib developed by Pfizer is a JAK3/TEC inhibitor that can inhibit IL-15 and CD-8 The signal transduction of cytokines, and these two cytokines are important factors that drive the immune system to kill hair follicle cells.

Ritlecitinib has shown gratifying effects in the phase 2 clinical trial of patients with alopecia areata, and has been granted a breakthrough therapy designation by the FDA.
The key phase 3 clinical results are expected to be available in the third quarter of this year.

This innovative treatment was also planned to be included in China in December last year as a breakthrough treatment product, and 4 clinical studies are currently underway in China.

▲Phase 2a clinical results of Ritlecitinib (picture Source: Pfizer's official website) In addition, Concert Pharmaceuticals' CTP-543 is an oral JAK1/2 inhibitor.

It is a deuterated ruxolitinib that can enhance the therapeutic properties of the drug by replacing the hydrogen atoms in the compound with heavy hydrogen atoms , Such as increasing the half-life in the body, improving oral availability, improving safety characteristics, etc.

CTP-543 has also been granted breakthrough therapy designation by the FDA, and has reached the primary efficacy endpoint in phase 2 clinical trials.

It is currently in phase 3 clinical trials.
Accept inspection during the test. ▲CTP-543 Phase 2 clinical trial results (picture source: Concert's official website) 50% of patients' blood glucose levels reached normal levels, and Eli Lilly’s innovative diabetes treatment reached the phase 3 clinical endpoint.
Eli Lilly recently announced its glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor dual agonist tirzepatide, reached the primary endpoint in a phase 3 clinical trial called SURPASS-2.

Compared with the active control group, the three different doses of tirzepatide significantly reduced the glycosylated hemoglobin (A1C) level and body weight of patients with type 2 diabetes.

In the group of patients who received the highest dose (15 mg), after 40 weeks of treatment, 50% of the patients had A1C levels that reached the level of normal people, and the average weight was reduced by 12.
4 kg.

Previously, tirzepatide had reached the primary endpoint in two phase 3 clinical trials.

Tirzepatide is one of the key development projects that Eli Lilly has high hopes for.
It is a GIP and GLP-1 receptor dual agonist injected once a week, which can integrate the effects of two incretins into one molecule.
It represents a new type of treatment for type 2 diabetes.

GIP is a hormone that may complement the effects of GLP-1 receptor agonists.

In preclinical models, GIP has been shown to reduce food intake and increase energy expenditure, thereby causing weight loss.
When used in combination with GLP-1 receptor agonists, it may have a greater impact on glucose levels and weight.

In this randomized open-label clinical trial, a total of 1,879 type 2 diabetic patients received tirzepatide or injectable semaglutide (semaglutide, 1 mg) in addition to metformin.

These patients had an average history of diabetes of 8.
6 years, and the use of metformin alone did not allow their blood sugar levels to be adequately controlled.

The test results showed that compared with the active control group, the three different doses (5 mg, 10 mg, and 15 mg) of tirzepatide all caused a greater degree of A1C and weight loss.
The specific values ​​are as follows. In the group of patients treated with tirzepatide at a dose of 15 mg.

92% of patients have A1C levels below 7%, which is the standard recommended by the American Diabetes Association for diabetic patients.

The A1C level of 50.
9% of patients was lower than 5.
7%, which is the standard for healthy people without diabetes.

▲The efficacy data of Tirzepatide in the SURPASS-2 clinical trial (data source: reference [5], graphed by WuXi AppTec's content team) The first biological therapy, Genentech IL-6 receptor inhibitor was approved to treat rare lung disease Roche (Roche) Genentech (Genentech) announced that the US FDA approved the IL-6 receptor inhibitor Actemra (tocilizumab) extended indications for the reduction of systemic sclerosis (scleroderma)-related interstitial lung disease (SSc- ILD) The rate of decline in lung function in adult patients.

The press release states that Actemra is the first biologic therapy approved by the FDA for the treatment of the disease.

Scleroderma is a rare disease that causes tissues throughout the body (including lungs and other organs) to thicken and form scar tissue.

Interstitial lung disease (ILD) is a disease that affects the interstitium of the lungs and is the most common manifestation of scleroderma.

SSc-ILD is a progressive lung disease in which lung function gradually declines and may be life-threatening.

ILD is the leading cause of death in patients with scleroderma.
Due to the gradual decline in lung function, the patient's lungs cannot provide enough oxygen to the heart.

Actemra is a humanized IL-6 receptor antagonist.

It has been approved for the treatment of patients with moderate to severe rheumatoid arthritis.

This approval is based on the results of a randomized, double-blind, placebo-controlled Phase 3 clinical trial.

In this study, compared with patients in the placebo group, patients receiving Actemra had a lower level of reduced forced vital capacity (FVC) at 48 weeks than in the control group.

FVC decreased by 14 ml in the Actemra group and 255 ml in the control group.

Note: This article is intended to introduce medical and health research, not to recommend treatment options.

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

Reference: [1] Merck KGaA, Darmstadt, Germany, Builds on Leadership in Head and Neck Cancer Through Worldwide Licensing Agreement with Debiopharm for Pivotal-Stage Xevinapant.
Retrieved March 1, 2021, from https:// news-releases/merck-kgaa-darmstadt-germany-builds-on-leadership-in-head-and-neck-cancer-through-worldwide-licensing-agreement-with-debiopharm-for-pivotal-stage-xevinapant-301237104.
html[2] FDA approves Oncopeptides' PEPAXTO® (melphalan flufenamide) for patients with relapsed or refractory multiple myeloma.
Retrieved February 28, 2021, from https:// pepaxto--melphalan-flufenamide-for-patients-with-relapsed-or-refractory-multiple-myeloma-301236751.
html[3] eGenesis Announces $125 Million Series C Financing.
Retrieved March 2, 2021, from https://www.
globenewswire.
com/news-release/2021/03/02/2185240/0/en/eGenesis-Announces-125-Million-Series-C-Financing.
html[4] Baricitinib is First JAK-Inhibitor to Demonstrate Hair Regrowth in Phase 3 Alopecia Areata (AA) Trial.
Retrieved March 3, 2021, from https:// -alopecia-areata-aa-trial-301239291.
html[5] Tirzepatide achieved superior A1C and body weight reductions across all three doses compared to injectable semaglutide in adults with type 2 diabetes.
Retrieved March 4, 2021, from https://investor .
lilly.
com/news-releases/news-release-details/tirzepatide-achieved-superior-a1c-and-body-weight-reductions[6] Genentech's Actemra Becomes the First Biologic Therapy Approved by the FDA for Slowing the Rate of Decline in Pulmonary Function in Adults With Systemic Sclerosis-Associated Interstitial Lung Disease, a Rare, Debilitating Condition.
Retrieved March 5, 2021, from https:// actemra-becomes-the-first-bio