PARP2

Armed with medical chemistry expertise, the biotech has worked to create better molecules against validated targets. A group of familiar faces to Incyte watchers has broken off to start their own biotech, pulling in $102 million to develop competitors to approved cancer drugs from AstraZeneca, GSK, Novartis and Pfizer. The biotech, Synnovation Therapeutics, was founded by Wenqing Yao, Ph.D., and Liangxing Wu, Ph.D. Yao spent 19 years at Incyte, rising to the post of head of discovery chemistry, before leaving and setting up Synnovation in 2021. Wu worked alongside Yao at Incyte, where he spent almost a decade to end up with the title executive director, medicinal chemistry. Armed with medical chemistry expertise that contributed to Incyte products such as Olumiant, Pemazyre and Tabrecta, the pair have worked to create better molecules against validated targets, namely PARP and PI3K. It is now almost 10 years since the first drugs against the targets were approved, with AstraZeneca and Merck & Co.’s PARP inhibitor Lynparza and Gilead’s PI3K inhibitor Zydelig both winning authorizations in 2014. Other companies have since secured approval for competitors to those first-in-class products but work to address the limitations of Lynparza and Zydelig is yet to yield a flawless therapy. Synnovation, which officially launched today, has identified hematologic toxicity as a weakness of first-generation PARP inhibitors. Like other companies, the biotech has fingered inhibition of PARP2 as the cause of the toxicity and bet that it can expand the therapeutic index by selectively targeting PARP1.  That isn’t a new idea. AstraZeneca has taken one selective PARP1 inhibitor, AZD5305, into phase 3 and moved its brain-penetrating sibling AZD9574 into the clinic. Gilead joined the race last year by acquiring XinThera and Merck KGaA has placed two PARP1 bets, one on Nerviano Medical Sciences and another on Jiangsu Hengrui Pharmaceuticals. Synnovation plans to start dosing patients in a phase 1 clinical trial of its brain-penetrating challenger, SNV1521, in the coming weeks. In preclinical tests, the biotech showed the molecule has greater than 500-fold selectivity against PARP2 and is more effective at inhibiting tumor growth than Lynparza. The biotech’s second candidate, SNV4818, is aimed at a target that has proven particularly troublesome. Zydelig and three other Gilead drugs that are too small to warrant their own line in the earnings collectively brought in $171 million over the first nine months of the year. Potential rivals have fled the space amid concerns PI3K inhibitors may shorten life expectancy and a resulting regulatory pushback.  Synnovation’s attempt to crack the PI3K puzzle has resulted in a molecule that targets the alpha form of the kinase and, according to the biotech, “is differentiated from competitor molecules by virtue of its excellent selectivity for H1047X and moderate selectivity over relevant E545/542X mutants.” The design reflects the belief that a lack of selectivity against wild type PI3K-alpha has held the class back to date.    Wu and Yao respectively work as CEO and senior vice president, drug discovery at Synnovation. The pair have been joined at the new biotech by two other leaders with lengthy stays at Incyte on their résumés. Phillip Liu, Ph.D., came on board as SVP, head of biology, while Kevin O’Hayer, M.D., Ph.D., took up the SVP, head of clinical development position last year.

Synnovation isn't breaking any new ground with the targets it is developing small molecules against; but instead, the cancer company aims to make a name for itself by being a best-in-class drug developer – and Third Rock partner Reid Huber is confident that CEO Wenqing Yao and his team can make that happen. Huber's firm led the biotech's $102-million series A, which closed Wednesday with participation from Nextech, Lilly Asia Ventures, Sirona Capital and Cormorant Asset Management. While the amount may seem eye-popping for such an early round, the funds will advance three experimental cancer treatments – a PARP1 inhibitor, a small molecule targeting mutant PI3Kα, and a third undisclosed programme – to the clinic by early 2025."It's rare that you get to have a multi-asset, multi-indication oncology company that's nearly clinical-stage across three programmes at the time of launch," Huber told FirstWord. But more so than the pipeline, it was the team behind Synnovation that enticed Third Rock to become a seed investor in 2023. Up until mid-2021, Yao was head of discovery chemistry at Incyte, where Huber served as chief scientific officer from 2011-2018. Together, they brought over 30 molecules into the clinic, while Yao’s tenure eventually produced five approved drugs: Jakafi (ruxolitinib), Olumiant (baricitinib), Pemazyre (pemigatinib), Tabrecta (capmatinib) and Opzelura (ruxolitinib)."Wenqing and his team are one of the strongest –  if not, arguably, over the last few decades, the strongest – highest output chemistry team there is in industry," Huber said. "It's rare to get one drug approved if you’re a fortunate scientist in industry; it's extremely rare to get five." Making drugs – not just clinical candidatesAt Synnovation, the team is approaching known targets with a best-in-class mentality. It's not enough for a compound to be selective and potent, Huber said. A best-in-class drug means a low-milligram dose, long half-life, and an improved safety profile, especially if the compound inhibits PARP, like Synnovation's lead candidate SNV1521."I think Wenqing's team knows the difference between a drug and a clinical candidate, and they're focused on making drugs," Huber added. All approved PARP inhibitors non-selectively hit both PARP1 and PARP2. The first protein most likely drives the therapies' efficacy to treat cancer, while scientists believe the second triggers the haematological toxicities that have limited the drug class' approved indications, as well as their use in combination with chemotherapy and other next-gen treatments like antibody-drug conjugates and radiotherapeutics. Synnovation's molecule selectively inhibits PARP1, which could open up a world of combinations. SNV1521 also penetrates the central nervous system, making it potentially viable to treat metastatic disease or even primary brain tumours. The compound is slated to start a clinical trial in mere weeks, Huber said. Following closely behind is SNV4818, which inhibits PI3Kα – another target that has been saddled with safety concerns. Synnovation's candidate zeros in on the enzyme's mutant form, as blocking the wild type can cause dose-limiting side effects, Huber said. The candidate is expected to enter the clinic in the fourth quarter.Synnovation has a third precision medicine programme as well against an undisclosed oncology target, with clinical testing also scheduled to start by year-end. Given Yao's impressive Incyte track record and the team's approach to best-in-class drug development, Huber believes Third Rock has placed a good bet on Synnovation. "There's an old adage that when you find a good jockey, you bet on the jockey," Huber said. "Wenqing and his team absolutely represent that great jockey."

SHANGHAI & CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Zai Lab Limited (NASDAQ: ZLAB; HKEX: 9688) today announced that the 2023 National Reimbursement Drug List (NRDL) released by China’s National Healthcare Security Administration (NHSA) has been updated to include the following medicines and indications: VYVGART® (efgartigimod alfa injection) is included for the first time in the NRDL for the treatment of adult patients with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody positive; NUZYRA® (omadacycline) is included for its oral formulation for the treatment of adults with community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI); and ZEJULA® (niraparib) is renewed for the maintenance treatment of adult patients with platinum-sensitive, first-line and recurrent ovarian cancer. “The initial NRDL inclusion for VYVGART is an especially important milestone for gMG patients and underscores the clinical value Zai Lab is delivering to the medical community and to patients in China,” said William Liang, Chief Commercial Officer of Zai Lab. “The addition of both VYVGART and NUZYRA (oral formulation) to the NRDL, as well as the renewal of previously included indications for ZEJULA, further supports patient access to these important medications throughout China at reduced prices, which significantly lower the cost of treatment for patients and their families.” “A key part of Zai Lab’s mission is to bring innovative medicines to patients with significant unmet medical needs in China and around the world,” said Josh Smiley, President and Chief Operating Officer of Zai Lab. “We are pleased that we now have four products included in the NRDL, and we will continue our efforts to expand patient access to our innovative treatments, including through NRDL coverage of different indications and formulations for our commercial products. We are grateful for this action by the NHSA, and we look forward to continuing to work with the NHSA to improve patient access and costs for high-quality treatments in China.” About Myasthenia Gravis in China Myasthenia gravis (MG) is a chronic autoimmune disease, characterized by debilitating and potentially life-threatening muscle weakness. There are approximately 170,000 people in China living with gMG1, and of those patients, 85% are estimated to have confirmed AChR antibodies; in this generalized form of the disease, skeletal muscles throughout the body may be affected, resulting in weakness and early fatigue. Difficulties with double vision, facial expression, speech, swallowing, and ambulation are frequent and difficult to manage for patients and treating physicians. In more life-threatening cases, gMG can affect the muscles responsible for breathing, which can be fatal. Acetylcholinesterase (AChE) inhibitors, steroids, immunosuppressants, and IVIg are the mainstay of treatment in China. These drugs often achieve only partial restoration of strength. 1 The growing burden of generalized myasthenia gravis: a population-based retrospective cohort study in Taiwan, 2023. About VYVGART VYVGART is an antibody fragment designed to reduce disease-causing immunoglobulin G (IgG) antibodies and block the IgG recycling process. Efgartigimod binds to the neonatal Fc receptor (FcRn), which is widely expressed throughout the body and plays a central role in rescuing IgG antibodies from degradation. The National Medical Products Administration (NMPA) approved VYVGART as an add on to standard therapy for the treatment of adult patients with gMG who are anti-AChR antibody positive in June 2023. VYVGART is the first approved FcRn blocker in China. We commercially launched VYVGART in China in September 2023. Zai Lab has an exclusive license from argenx to develop and commercialize efgartigimod in mainland China, Hong Kong, Macau, and Taiwan (Greater China). About CABP and ABSSSI in China CABP is the most common type of pneumonia that is acquired outside of the hospital. It is one of the most common infectious diseases and is a significant cause of mortality and morbidity worldwide. ABSSSI are bacterial infections of skin and associated soft tissues, such as loose connective tissue and mucous membranes. ABSSSI are common and encompass a variety of disease presentations and degrees of severity. In 2020, the estimated incidence of CABP in mainland China was approximately 10 million patients2, and in 2015, the estimated incidence of ABSSSI was 2.8 million patients3. There are significant unmet needs for broad-spectrum antibiotics addressing multi-drug resistance (MDR) infections with a favorable safety profile. 2 Incidence of community-acquired pneumonia in urban China: A national population-based study, 2020. 3 2015 estimates, Zai Lab analysis. About NUZYRA NUZYRA, a novel tetracycline-class antibacterial with both once-daily oral and IV formulations, is specifically designed to overcome tetracycline resistance and to improve activity across a broad spectrum of bacterial infections, such as those caused by Gram-positive, Gram-negative, atypical, and many other pathogens. The NMPA approved NUZYRA as a Category 1 innovative drug for both oral and IV formulations for the treatment of CABP and ABSSSI in adult patients in December 2021. It was included in the NRDL for the first time in January 2023 for the treatment of CABP and ABSSSI for IV formulation, and it will be added to the NRDL in January 2024 for the treatment of CABP and ABSSSI for oral formulation. Zai Lab has an exclusive license from Paratek Pharmaceuticals, Inc. to develop, manufacture, and commercialize NUZYRA in Greater China. About Ovarian Cancer in China Ovarian cancer is one of the most common gynecologic cancers in China, with over 55,000 newly diagnosed cases and 37,000 deaths in China annually4. While platinum-based chemotherapy is effective at inducing an initial response in ovarian cancer, the disease will recur in the majority of women. Effective treatment options for patients with platinum-sensitive recurrent ovarian cancer remain limited. New agents that prolong the duration of response following first-line platinum-based treatment and delay the relapse of ovarian cancer will benefit patients with ovarian cancer in China. 4 Globocan 2020. About ZEJULA ZEJULA (niraparib) is an oral, once-daily small-molecule poly (ADP-ribose) polymerase (PARP) 1/2 inhibitor. A PARP inhibitor blocks the ability of cancer cells to repair themselves after they have been damaged by radiation and certain chemotherapies. This inhibition of DNA damage repair can result in the inability of cancer cells to replicate themselves and in programmed cell death. Tumors that are deficient in key DNA damage repair pathways, such as BRCA1 mutant tumors, are particularly sensitive to ZEJULA. As maintenance therapy, ZEJULA is for women who have had prior chemotherapy treatment but are at high risk of cancer recurrence. ZEJULA is intended to avoid or slow a recurrence of the cancer if it is in remission after prior treatment. In the maintenance setting, ZEJULA does not require the addition of radiation or chemotherapies to kill tumor cells. As a first-line monotherapy maintenance treatment of patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer (collectively, ovarian cancer) following a response to platinum-based chemotherapy, ZEJULA was approved by the NMPA in September 2020 and included in the NRDL in December 2021. As a maintenance treatment of patients with platinum sensitive recurrent ovarian cancer, ZEJULA was approved by the NMPA in December 2019 and included in the NRDL in December 2020. Zai Lab has an exclusive license from GlaxoSmithKline to develop and commercialize ZEJULA in mainland China, Hong Kong, and Macau. About Zai Lab Zai Lab (NASDAQ: ZLAB; HKEX: 9688) is an innovative, research-based, commercial-stage biopharmaceutical company based in China and the United States. We are focused on discovering, developing, and commercializing innovative products that address medical conditions with significant unmet needs in the areas of oncology, autoimmune disorders, infectious diseases, and neuroscience. Our goal is to leverage our competencies and resources to positively impact human health in China and worldwide. For additional information about Zai Lab, please visit or follow us at . Zai Lab Forward-Looking Statements This press release contains forward-looking statements about future expectations, plans, and prospects for Zai Lab, including, without limitation, statements relating to the benefits of and increased patient access to VYVGART (efgartigimod alfa injection), NUZYRA (omadacycline), and ZEJULA (niraparib); the treatment of gMG, CAPB, and ovarian cancer in Greater China; and regulatory discussions, submissions, filings, and approvals and the timing thereof. These forward-looking statements may contain words such as “aim,” “anticipate,” “believe,” “could,” “estimate,” “expect,” “forecast,” “goal,” “intend,” “may,” “plan,” “possible,” “potential,” “will,” “would,” and other similar expressions. Such statements constitute forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements are not statements of historical fact or guarantees or assurances of future performance. Forward-looking statements are based on our expectations and assumptions as of the date of this press release and are subject to inherent uncertainties, risks and changes in circumstances that may differ materially from those contemplated by the forward-looking statements. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including but not limited to (1) our ability to successfully commercialize and generate revenue from our approved products; (2) our ability to obtain funding for our operations and business initiatives, (3) the results of our clinical and pre-clinical development of our product candidates, (4) the content and timing of decisions made by the relevant regulatory authorities regarding regulatory approvals of our product candidates, (5) risks related to doing business in China, and (6) other factors identified in our most recent annual and quarterly reports and in other reports we have filed with the U.S. Securities and Exchange Commission. We anticipate that subsequent events and developments will cause our expectations and assumptions to change, and we undertake no obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as may be required by law. These forward-looking statements should not be relied upon as representing our views as of any date subsequent to the date of this press release. Our SEC filings can be found on our website at and on the SEC’s website at . View source version on businesswire.com: Contacts For more information, please contact: Investor Relations: Christine Chiou / Lina Zhang +1 (917) 886-6929 / +86 136 8257 6943 christine.chiou1@zailaboratory.com / lina.zhang@zailaboratory.com Media: Shaun Maccoun / Xiaoyu Chen +1 (415) 317-7255 / +86 185 0015 5011 shaun.maccoun@zailaboratory.com / xiaoyu.chen@zailaboratory.com Source: Zai Lab Limited View this news release online at: