Saisheng Pharmaceutical: New Journey of Innovative Drug Development

On August 20th, Saisheng Pharmaceutical released its 2021 interim results.

On July 14, the marketing application for Nacituzumab submitted by Saisheng Pharmaceutical was accepted by the CDE and entered the approval process, which will soon bring a breakthrough new therapy for domestic neuroblastoma patients

There is no doubt that Cetuzumab will be the beginning of Saisheng Pharmaceutical to accelerate the transformation of innovative drugs

Innovation and transformation: avoid overcrowded track, focus on truly unsatisfied clinical

In recent years, Saisheng Pharmaceutical has taken frequent actions in the field of innovative drugs and has continued to increase

1.

Source: NextPharma

Neuroblastoma (Neuroblastoma, NB) is an immature embryonic cell originating from the adrenal medulla or paravertebral sympathetic ganglia.

High-risk neuroblastoma is more aggressive and has a poor prognosis, with a 5-year overall survival rate of less than 50%

Narcetuzumab and Omburtamab are expected to bring better treatment effects and experience for patients with high-risk neuroblastoma

In November 2020, natalizumab was approved by the FDA for the first time in combination with granulocyte-macrophage colony stimulating factor (GM-CSF) for relapse/difficulty that showed partial remission, mild remission, or stable disease on previous treatments Treatment of high-risk neuroblastoma in children (1 year and older) and adult patients

In clinical studies supporting accelerated approval, narcetumab treats relapsed and refractory high-risk neuroblastoma (Study 12-230) and relapsed or refractory high-risk neuroblastoma in bone or bone marrow (Study 201).

In addition to the significant clinical benefits, natalizumab also has advantages in clinical administration convenience and patient compliance

In February 2021, narcetuzumab officially achieved commercial sales in the United States

In addition to relapsed and refractory high-risk neuroblastoma, the treatment line of narcetumab is also gradually advancing, and continues to expand other indications such as osteosarcoma, and its commercial value is expected to be further realized

Source: Ymabs website

2.

In April 2021, Y-mAbs Therapeutics (NASDAQ: YMAB), a partner of Saisheng Pharmaceuticals, submitted a marketing application (MAA) for omburtamab to the European Medicines Agency (EMA) for the treatment of children’s central nervous system/pia mater Neuroblastoma
.
According to NextPharma's data, Omburtamab is the first B7-H3 drug submitted for marketing and is expected to become the First in class product
.

Part of the clinical development stage of B7-H3 drugs (Source: NextPharma)

In addition to the first-mover advantage, the clinical potential of Omburtamab cannot be underestimated
.
According to published clinical data, Omburtamab has significantly improved the median survival time by about 6 times compared with treatment data reported in the literature and clinical studies in neuroblastoma with central/pia material metastasis (CNS/LM NB), 26 The weekly disease control rate reached 90%
.

Source: Ymabs website

In terms of development strategy, Omburtamab also chose the same strategy as narcetuzumab
.
First target neuroblastoma that lacks innovative drugs in the field of orphan drugs, and then gradually expand to the frontline or more indications for patients, such as diffuse endogenous pontine glioma (DIPG) and connective tissue proliferative small Round cell tumor (DSRCT)
.

Source: Ymabs website

3.
RRx-001

RRx-001 is a small-molecule CD47 drug that is very distinctive in the pipeline products of Saisheng Pharmaceutical and has the first in class potential
.
At present, the global research of RRx-001 has progressed to clinical phase III, and the country has also obtained the clinical implied license of CDE for the treatment of extensive-stage small cell lung cancer
.

RRx-001 was previously used as a synthetic intermediate for explosives or rocket fuel.
Under the keen intuition and determination of Professor Mark Bednarski, a chemist suffering from bowel cancer, it has been applied in the field of oncology
.
In recent years, with the progress of research, it has been found that RRx-001 can reduce the levels of CD47 and PD-L1 mRNA and related proteins, and enhance the phagocytosis and percentage of tumor cells by macrophages, and stimulate anti-tumor immune responses [3.
4]
.
The results of the use of clinical cases also showed that the pseudo-disease progression and immune cell infiltration similar to PD-1/L1 immunotherapy occurred with RRx-001 treatment [5.
6], proving that it is indeed involved in immune regulation
.

RRx-001 treatment appeared false progress (PET/CT scan, A: left liver lobe showed diffuse background, no discrete lesions
.
Right liver lobe showed lesions; B: After 3 doses of RRx001 treatment, how much left liver lobe A discrete large lesion with enlarged right lobe lesions; C: After receiving 2 cycles of platinum combined therapy, liver lesions were extensively resolved, and the metabolic response was complete, which was close to the tissue background level)

CD47.
, also known as integrin-related protein, is a widely expressed transmembrane glycoprotein
.
Tumor cells express CD47.
and bind to the signal regulatory protein α (SIRPa) on the surface of macrophages to send a "Do not eat me" signal to macrophages to escape the body's immune system
.
Combining with PD-L1 and PD1 on the surface of T cells, it releases a signal similar to "Do not find me", which is known as the next "PD-1"
.

RRx-001 is currently the only small molecule drug among the products involved in the CD47 signaling pathway in the world
.
Different from the earliest deployment of antibody drugs in hematomas, RRx-001 has shown significant efficacy in the treatment of solid tumors such as colon cancer (CRC) and small cell lung cancer (SCLC)
.
Clinical Phase II data showed that RRx-001 significantly prolonged the median progression-free survival (mPFS) and overall survival (mOS) of CRC patients by 5.
7 months and 2.
5 months, respectively; in the third-line treatment of SCLC, mPFS And mOS also reached 6.
4 months and 8.
6 months, respectively
.

RRx-001 also shows certain advantages in safety, especially the occurrence of anemia has not been reported
.
In addition, RRx-001 is administered by injection, which undoubtedly has better acceptance and compliance compared to intravenous infusion of antibody drugs
.
It is important that the small molecule drug RRx-001 is prepared by chemical synthesis, and it has advantages in cost control compared to antibody drugs in terms of the convenience of raw materials, process maturity, production batch size, and impurity types.
If it can be realized The same therapeutic effect is of course self-evident in terms of patient accessibility
.

4.
PEN-866

PEN-866 is a small molecule conjugate drug (SMDC) developed by Saisheng Pharmaceutical.
It is currently undergoing a Phase II basket test for solid tumors in the United States
.

Antibody-conjugated drugs (ADC) are undoubtedly the representative of conjugated drugs that have received the most attention nowadays.
The therapeutic breakthroughs and transactions of listed and clinical drugs have also attracted much attention; however, the shortcomings of ADC drugs are also obvious, such as the inability to target intracellular proteins, complex production processes and regulatory challenges
.

Unlike ADC, SMDC achieves targeted positioning through small molecules and accurately releases drugs, which is also a potential branch in the coupled drug track
.
SMDC and ADC drugs have similar design concepts and mechanisms of action, but SMDC still has the potential to penetrate cell membranes and target intracellular proteins
.
On the other hand, in terms of the external manifestation of the drug itself, SMDC is not much different from traditional chemicals
.
Therefore, there are long-term accumulated practical experience in many aspects such as cost control, production capacity guarantee, regulatory compliance, and clinical use
.

PEN-866 structure

Importantly, SMDC has similar advantages as ADC in clinical performance, especially the control of adverse reactions
.
PEN-866 binds to the intracellular target heat shock protein 90 (HSP90) through selective small molecules to carry the active metabolite SN-38 of the toxin topoisomerase inhibitor irinotecan into the tumor and accumulate and stay, SN -38 is cleaved and released over time, avoiding adverse reactions caused by systemic exposure of irinotecan (which metabolizes SN-38)
.
Clinical data showed that at the recommended dose of PEN-866 (175 mg/m2), no DLT was observed, and only one patient experienced uncomplicated G3 transient neutropenia, which was compared with irinote In terms of 53.
8% of neutropenia events ≥ grade 3, the safety advantage is significant
.

In general, Saisheng Pharmaceutical’s innovative drug pipeline layout reflects the gradient layout of early, middle and late products, and has long-term development potential
.
However, in order to realize the domestic landing and listing of products and realize the commercial value, Saisheng Pharmaceutical's own research and development capabilities are also crucial
.
Saisheng Pharmaceutical introduced the company's leading R&D talents early last year.
Dr.
Guo Xiaoning, who has many years of clinical development experience in multinational pharmaceutical companies and international CROs, has built a clinical research team of nearly 100 people
.
The efficient execution and development capabilities of the clinical research team will promote the rapid launch of innovative products
.
The new dosage form of antifungal drug Nomico (miconazole oral patch), which was just approved in the first quarter of this year, was completed by the clinical development team built by Saisheng to complete Phase III clinical trials and promote it to market.
This is about to begin commercialization.
The new drug is expected to become a new growth point for Saisheng Pharmaceutical
.
It has only been more than seven months from the introduction of narcetuomab to the submission of the marketing application.
Its rapid launch may be a good signal, and it also demonstrates the significant improvement in the clinical development capabilities of Saisheng Pharmaceutical, which is important for other late-stage products.
Clinical development is also a strong guarantee
.

Commercialization ability: mature experience blessing, integrated platform help

Compared with the Biotech companies that started from scratch, traditional pharmaceutical companies often have some unique advantages in transforming into innovative drugs, such as stable and substantial R&D funding guarantees, competent business teams and mature business networks
.
These points are also reflected in Saisheng Pharmaceutical
.

Ridaxian is the original thymus method developed by Saisheng Pharmaceutical Co.
, Ltd.
in Italy.
It has been sold in more than 30 countries around the world.
It is the first new innovative product of thymus method to be marketed and commercialized in China
.
With both market insight and continuous evolutionary commercialization capabilities, Saisheng Pharmaceutical always has an advantage in market competition.
From 2017 to 2019, the annual compound growth rate of Nidaxian has exceeded 10%
.
These results fully show that even in the face of generic competition, the commercialization strength of Saisheng Pharmaceutical is still strong
.

The early commercial promotion of Ridaxian has exercised Saisheng Pharmaceutical's ability and experience in the commercialization of innovative drugs, and helped Saisheng Pharmaceutical complete the exploration of commercialization paths
.
In recent years, in the face of the new market environment, Saisheng Pharmaceutical has created an innovative GTP (GO-TO-PATIENT) business model, combining online and offline, improving the accessibility of medicines, expanding the coverage of patients, and once again tempering itself The core business development capabilities in the two high-value and high-growth therapeutic areas of tumors and severe infections
.

In addition, Saisheng Pharmaceutical has established a marketing team of more than 700 people and a sales network covering more than 2,000 domestic hospitals and more than 800 DTP pharmacies, which can effectively guarantee the commercialization of innovative drugs
.
At the same time, Saisheng Pharmaceutical has also established an integrated platform integrating product development and commercialization, which will surely provide assistance in the commercialization of innovative drug products
.

Concluding remarks

As a commercialization stage company with mature listed products, Saisheng Pharmaceutical has a stable cash flow and a strong business network, and its profitability and operating efficiency are much higher than the industry average.
This will be the innovative drug of Saisheng Pharmaceutical.
Transformation provides a strong guarantee
.

By focusing on unmet clinical needs in the areas of infection and oncology, Saisheng Pharmaceutical has initially built an innovative drug project portfolio with a clear development schedule
.
At the same time, it is the first in China to deploy differentiated innovative products such as antibodies with BIC or FIC potential, antibody radiotherapy, small molecule CD47 and SMDC
.
It can be said that Saisheng Pharmaceutical has a competitive advantage in the transformation and long-term development of innovative drugs
.

Reference

1.
Xia Jianfeng et al.
Research progress in clinical diagnosis and treatment of neuroblastoma in children.
Medical review, 2020.
26(4): 690-694

2.
Lu Dongfang et al.
Research progress in molecular genetics characteristics of high-risk neuroblasts.
Chinese Pediatric Surgery, 2021.
42(1): 81-87

3.
MYC Regulates the Anti-Tumor Immune Response through CD47 and PD-L1.
Science.
2016 April 8; 352(6282): 227–231

4.
RRx-001 Acts as a Dual Small Molecule Checkpoint Inhibitor by Downregulating CD47 on Cancer Cells and SIRP-α on Monocytes / Macrophages.
Translational Oncology (2019) 12.
626–632

5.
Complete metabolic response of metastatic castration‐resistant neuroendocrine carcinoma of the prostate after treatment with RRx‐001 and reintroduced platinum doublets.
Clin Case Rep.
2018;6:2478–2481

6.
Immune Reactivity and Pseudoprogression or Tumor Flare in a Serially Biopsied Neuroendocrine Patient Treated with the Epigenetic Agent RRx-001.
Case Rep Oncol.
2016 Jan-Apr; 9(1): 164–170.