Junshi/British PARP inhibitor senaparib: Create the best-in-class new drug for "synthetic death".

ASAP inhibitors, as a hot topic for the development of new drugs in the field of oncology, have also presented a number of ground-breaking and significant research results at the Global Medical Conference in recent years.
, for example, at the CSCO 2018 conference, Nirapali showed therapeutic effect on ovarian cancer patients with or not carrying BRCA mutations; Clinical data release, for the PARP inhibitors to lay the foundation for the expansion of the evidence of adaptation, ESMO2020 Conference, in addition to foreign PARP inhibitors continue to work, domestic PARP inhibitors also began to show potential, re-Ding (Nirapali, listed), Hengrui (Fluopali, NDA), Baiji Shenzhou (Pamipali, NDA), Junshi / Yingpai (senaparib, Clinical PHASE III) with the competition.
the successful application of the concept of
PARP inhibitor: "synthetic lethality", the market forecasts more than $10 billion in PARP, or poly-ADP-ribose polymerase, a class of catalytic poly-ADP nuclei present in the epinucle cells Glyco-poly (ADP-ribose), PAR-based nucleases, belonging to a key DNA repair enzyme, including PARP1, PARP2, PARP3 and other 18 members, play an important role in DNA damage response and repair, regulation of apoptosis, and maintenance of genomic stability.
PARP inhibitors are the most successful example of the use of the anti-tumor concept of "synthetic death" in the development of new drugs.
synthetic lethality refers to the simultaneous suppression of two non-lethal genes, leading to cell death.
use this mechanism to find specific mutations in the tumor, and then find its "synthetically lethal" partner, which in turn specifically kills cancer cells.
PARP inhibitors are the first drugs to be clinically successful using the concept of synthetic lethality.
the key factor for the effectiveness of
PARP inhibitors is that tumor cells have iso-recombinant repair defects (HRD), and BRCA protein is an important protein in the same-origin recombinant repair process, so if the tumor cells appear BRCA1/2 gene mutations, the inhibition of PARP is better.
Nat Rev Clin Oncol. 2015 Jan;12 (1): 27-41 There are currently four PARP inhibitors on the market worldwide, namely Olapali (AstraZeneca), Rucapali (Clovis), Nirapali (GSK/Tesaro/Redding) and Helapali (Pfizer), and fluoropari (Henri) and Parmipali (Broadway) have also submitted listing applications to NMPA.
2019, the global PARP inhibitor market has exceeded US$1.6 billion and the market is still growing rapidly, with PARP's global sales expected to exceed US$12.3 billion and China's market sales reaching US$4.4 billion by 2030, according to Frost Sullivan.
Source: Company Earnings, Medicine Rubik's Cube Prospects Unlimited: Covering Multiple Tumors, Ideal Partner of Combined Therapy In 2014, Olapali was approved for the first adaptation of BRCA mutations after third-line and above chemotherapy, officially declaring the development of PARP inhibitors a success.
to date, PARP inhibitors have been approved for breast cancer, pancreatic cancer, prostate cancer, ovarian cancer, fallopian tube cancer, peritometric cancer and other adaptations, in the clinical development stage of the adaptation also includes stomach cancer, non-small cell lung cancer, colorectal cancer, small cell lung cancer, etc. , it can be said that PARP inhibitors cover a number of common high-risk tumors around the world.
the potential of PARP inhibition is not only expressed in the field of treatment, but also in the depth of the impact on tumor treatment.
ESMO 2020 meeting, Olapali released five-year follow-up data from a SOLO-1 study that showed that Olapali was able to achieve 56 months of ultra-long PFS in ovarian cancer patients with BRCA mutations, with 48.3 percent of patients without progression for five years, reducing the risk of disease progression or death by 67 percent.
does this data say? It is no exaggeration to say that nearly half of patients with BRCA mutant ovarian cancer treated with Olapali have a fully controlled disease within five years and the tumor shows no signs of deterioration, which, it is no exaggeration to say, has taken a major step towards a "clinical cure".
It is precisely because of the excellent clinical efficacy, PARP inhibitors in the clinical guidelines of drug recommendations continue to move forward, from the initial three-line treatment of drugs, to now a number of first-line drug qualifications, these are indicative that PARP inhibitors on tumor treatment has had an important and positive impact.
addition, as the scope of clinical use expands, or when the tumor develops obtained resistance, PARP inhibitors in association with other drugs have once again shown encouraging therapeutic results.
in this regard, PARPi can also be combined with chemotherapy, immunotherapy and targeted drugs, hoping to achieve greater therapeutic value and effectiveness through synergies and complementary mechanisms.
, but limited by the toxicity of overlays, especially the hematological toxicity inherent in PARP targets, no combination therapy of PARP and chemotherapy has been successful.
In addition to the familiar Olapali, Nirapali, Fluoropali and Parmipali,
's PARP inhibitors at this year's ESMO Conference are more interesting than the senaparib jointly developed by Regent Bio/EngPai Pharmaceuticals, which announced a joint venture with British Pharmaceuticals to inject no more than 300 million yuan into the joint venture to develop senaparib in China.
is junshi biology willing to bet on serenaparib? What is the competitive advantage of this drug? Take a look at the data released byenaparib at the ESMO conference with questions.
senaparib: Creating a new high ground for the "safety" of PARP inhibitors Senaparib launched Phase I clinical studies simultaneously in China and Australia in 2017, and the first patients were given the drug in November 2019 and January 2020, respectively, in the Registered Phase II and Validated Phase III studies in China.
the ESMO conference is the latest data from Senaparib's Phase I study in China and Australia.
Phase I study focused on assessing the tolerance, safety, PK and initial anti-tumor activity ofenaparib.
two trials were conducted using the standard 3-3 design modified Fibonacci method, divided into two queues of dose increment and expansion.
take the senaparib capsule once a day for 3 weeks for 1 cycle until the disease progresses or becomes inlerable.
clinical studies in China, in addition to ovarian cancer, fallopian tube cancer and primary peritometrial cancer, patients need to have BRCA-positive mutations during the expansion phase.
and histological or cytological examinations confirmed that there were at least ≥1 assessable or measureable lesions (according to RECIST 1.1) in difficult-to-treat malignant, advanced solid tumors that failed to be treated with at least first-line systemic systemic standard therapy.
results show that senaparib has potentially powerful anti-tumor effects.
In clinical studies in Australia, the disease control rate (DCR) was 89.5 per cent, with 2 out of 17 assessable BRCA-plus patients achieving partial remission, 1 case of BRCA-ovarian cancer patients with PR for more than 20 months, and 1 case of BRCA-prostate cancer patients with PSA levels decreasing by 50 per cent for 11 months.
clinical studies in China, 9 patients achieved partial remission (RECIST 1.1), ORR was 22% and DCR was 63.4%.
6 of these patients were BRCA mutations, so in BRCA mutation patients (25 cases), senaparib's ORR was 24%.
, the exposure of senaparib increased proportionally with the dose (2 mg-80 mg) and the high dose group showed a saturation trend (80 mg, 100 mg and 120 mg).
based on a comprehensive analysis of toxicity, pharmacodynamics and efficacy, the recommended daily oral senaparib 100mg was determined to be the recommended dose for Phase II (RP2D).
Australian Clinical Effectiveness Data China Clinical Effectiveness Data Safety, senaparib was generally controllable and tolerable in patients in both countries, and dose-limiting toxicity (DLT) was not observed.
The most common TRAEs in Chinese patients were a decrease in white blood cell count (43.4%), a decrease in plateplate count (26.4%), a decrease in hemoglobin (24.5%), anemia (24.5%), a decrease in appetite (24.5%) and fatigue (24.5%).
most TRAEs were level 1 or 2, 17 ≥3 levels of TRAE and 6 treatment-related SAEs were observed, and dose-limiting toxicity (DLT) was not observed.
, senaparib showed initial anti-tumor activity and excellent safety tolerance in both Australian and Chinese patients.
From the Phase I data, senaparib shows initial anti-tumor effects, since the data are obtained at a non-optimal dose, the therapeutic potential of senaparib may be further demonstrated in subsequent clinical studies, and the return to the core purpose of the Phase I study "proving drug safety and tolerance", does senaparib show an advantage? The adverse reactions of PARP inhibitors are similar but have their own characteristics, mainly related to differences in the capture ability, bone marrow/blood concentration distribution and off-target effect of different PARP inhibitors.
In April 2020, at the 3rd PARPi Summit Forum, Professor Huang Ping and other experts generally agreed that Olapali is the best choice for PARPi today, whether it is a balance of efficacy and safety, or simply a safety issue, so is senaparib safer than Olapali or other PARP inhibitors? First of all, senaparib showed high activity and wider treatment window in the clinic, compared with the other three PARP inhibitors, the recommended dose of senaparib Phase II administration (RP2D) is almost the lowest, indicating that IMP4297 on PARP inhibition activity is strong, although the lowest dose (1 mg), but has been close to its maximum tolerable dose (1.1 mg).
in the two clinics disclosed above, IMP4297 was given a maximum of 10 doses (2 mg-150 mg) increments, but dose-limiting toxicity (DLT) was not observed at 150 mg.
IMP4297 has begun to show anti-tumor vitality at 20 mg, showing a 7.5x treatment window, much higher than other PARP inhibitors, indicating greater flexibility in dose selection in clinical use.
, senaparib had a higher PARP inhibitory activity, but did not increase the associated hemotoxicity.
in terms of non-hemotoxicity, including nausea, constipation, vomiting, abdominal pain, diarrhea, etc., there are few levels or more of this toxicity, showing the potential to be superior to other PARP inhibitors.
patients in the treatment process, IMP4297 drug dose reduction or suspension rate is 15% and 5%, is relative to the lowest value of listed drugs.
further demonstrates that the IMP4297 is safe and toned.
PARP inhibitors are currently mainly used for maintenance therapy after chemotherapy, tumor patients may be poor before treatment, after chemotherapy, the physical condition is more changed, which requires that the treatment drugs in the anti-tumor effect at the same time, should have better safety and tolerance, in this regard, senaparib already has an advantage.
In addition, as the Olapali SOLO-1 trial confirms, patients have a possible long-term drug need, so good drug safety and tolerability are critical, and combined medication is a preferred option as a strategy to tap the potential of PARP therapy.
of treatment options and safety, as shown by Senaparib, will undoubtedly have a positive effect on combined drug use.
it is understood that British Pie has launched a clinical Phase 1 study on the combination of senaparib and the chemotherapy drug TMZ to treat small cell lung cancer overseas to explore the potential of senaparib in combination.
, Senaparib excels in safety and tolerance, even with the potential for best-in-class drugs, based on the data currently disclosed.
, can Senaparib eventually become best-in-Class? Let's wait and see the efficacy data for its Phase II and Phase III.
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