According to the expected target date of PDUFA, it is expected that in November, the US FDA will make regulatory decisions on the approval of six innovative drugs. This article will introduce these therapies.

Active ingredient: Zenocutuzumab
Indications: NRG1 positive non-small cell lung cancer (NSCLC) or pancreatic cancer
Company Name: Merus
Zenocutuzumab is a bispecific antibody targeting HER2 and HER3, which exhibits potential therapeutic efficacy against NRG1+cancer by uniquely binding to HER2 and effectively blocking the interaction between HER3 and NRG1 or NRG1 fusion protein. Preclinical studies have shown that zenocutuzumab can strongly inhibit the formation of HER2/HER3 heterodimers, thereby suppressing oncogenic signaling pathways, preventing tumor cell proliferation, and blocking tumor cell survival. Clinical studies have shown that it has anti-tumor activity in various types of NRG1+cancer.
According to the mid-term data from the recently released Phase 1/2 clinical trial, zenocutuzumab has shown persistent efficacy in the treatment of advanced NRG1+non-small cell lung cancer and pancreatic ductal adenocarcinoma (PDAC). The experimental results showed that in patients with advanced NRG1+non-small cell lung cancer, the overall response rate (ORR) evaluated by RECIST version 1.1 was 37.2% (29/78; 95% CI, 26.5-48.9), and the median duration of response (DOR) was 14.9 months. In advanced NRG1+pancreatic ductal adenocarcinoma, the ORR evaluated by RECIST version 1.1 was 42.4% (95% CI, 25.5-60.8); One patient (3%) achieved complete remission, 13 patients (39%) achieved partial remission, and 82% of patients had tumor shrinkage. The median DOR was 9.1 months (95% CI, 5.5-12.0).

Active ingredient: Eladocagene exuparvovec (trade name: Upstaza)
Indication: Aromatic L-amino acid decarboxylase deficiency (AADCD)
Company Name: PTC Therapeutics
Upstaza is a gene therapy based on the adeno-associated virus 2 (AAV2) vector, carrying the normal human DDC gene. It aims to deliver the normally functioning DDC gene directly into the brain's putamen through a one-time treatment, increasing the level of aromatic L-amino acid decarboxylase and restoring dopamine production.
The efficacy and safety features of Upstaza have been validated in multiple clinical trials and compassionate medication programs, with the first patient receiving treatment in 2010. In clinical studies, patients who fail to achieve the expected milestone in motor development can observe clinically significant improvement in motor function as early as 3 months after receiving treatment, and this transition continues for more than 5 years after receiving treatment. In addition, the cognitive abilities of all patients receiving treatment have improved. The results of the clinical trial have been published in the Molecular Therapy journal. In 2022, it was first approved for market by the European Commission, becoming the first approved gene therapy directly injected into the brain and the first approved therapy to change the course of AADCD disease.

Active ingredient: Obecabtagene autoleucel (obe cel)
Indication: B-cell acute lymphoblastic leukemia (ALL)
Company Name: Autolus Therapeutics
Obe cel is an autologous CAR-T cell therapy targeting the CD19 antigen. It aims to overcome the limitations of current CAR-T cell therapies in terms of clinical activity and safety. Its uniqueness lies in the fact that the designed chimeric antigen receptor has a fast off rate after binding to CD19, which can minimize the excessive activation of T cells, reduce toxic side effects, and prevent T cell exhaustion, thus improving the durability of CAR-T therapy.
In a critical phase 2 clinical trial, FELIX, obe cel demonstrated significant efficacy in patients with relapsed/refractory B-cell ALL. Data shows that among the 94 patients receiving treatment, 76% achieved complete remission (CR) or CR with incomplete hematological recovery (CRi). In this patient cohort, 112 adult patients were enrolled, of which 94 patients received treatment. Among patients who achieved remission, 97% did not detect minimal residual disease (MRD). In addition, at a median follow-up period of 9.5 months, 61% of patients who achieved remission maintained remission without receiving new anti-cancer therapy.
Previously, obe cel has been granted orphan drug status by the US FDA and the European Medicines Agency (EMA), as well as advanced regenerative medicine therapy (RMAT) certification by the US FDA and PRIME certification by EMA for the treatment of adult relapsed/refractory B-cell acute lymphoblastic leukemia.

Active ingredient: Govorestat
Indications: Galactosamia
Company Name: Applied Therapeutics
Govorestat (AT-007) is an aldose reductase inhibitor with central nervous system (CNS) permeability that can prevent the conversion of glucose to sorbitol. It is currently being developed for the treatment of several rare neurological disorders, including galactosemia, SORD deficiency, and phosphomannose mutase 2- congenital glycosylation disorder (PMM2-CDG).
The clinical trial results showed that patients receiving govorestat treatment experienced improvements in daily living activities, behavioral symptoms, cognition, fine motor skills, and tremors. Govorestat also significantly reduced plasma levels of lactitol in adults and children with galactosemia. Lactitol is a toxic metabolite that can cause tissue damage and long-term complications in patients with galactosemia.
It is worth mentioning that govorestat has been granted orphan drug status, pediatric rare disease status, and fast track status by the US FDA for the treatment of galactosemia. According to the press release, if approved, govorestat will become the first drug for treating galactosemia.

Active ingredient: Acoramidis
Indication: Transthyroid hormone protein mediated amyloidosis with cardiomyopathy (ATTR-CM)
Company Name: BridgeBio
Acoramidis is a new generation, orally administered, highly efficient transthyretin (TTR) small molecule stabilizer. It aims to simulate the protective function of TTR T119M mutation, maintain the normal tetramer conformation of TTR protein, and prevent the production of toxic amyloid protein.
The results previously published by BridgeBio showed that acoramidis treatment significantly increased and stabilized serum TTR levels on day 28 of treatment, and was associated with reduced overall mortality (ACM), cardiovascular mortality (CVM), and cardiovascular hospitalization (CVH) risk in ATTR-CM subjects at month 30. This therapy has been evaluated by industry media as a key therapy that may be approved for market in 2024. BridgeBio's previous press release also stated that acoramidis has the potential to become a heavyweight therapy.

Active ingredient: Zanidatamab
Indications: Treatment, unresectable, locally advanced or metastatic HER2 positive cholangiocarcinoma (BTC)
Company name: Jazz Pharmaceuticals, Zymeworks
Zanidatamab is a HER2 targeted bispecific antibody with a novel mechanism of action, which can target two distinct antigenic epitopes on the HER2 protein. The binding of Zanidatamab to HER2 can block its signaling, promote HER2 removal from the cell surface, and has been shown to have anti-tumor activity in several cancers expressing HER2, whether as a monotherapy or in combination with chemotherapy or other drugs.
The results of the Phase 2b clinical trial showed that in patients with HER2 positive biliary tract cancer treated with zanidatamab, the confirmed objective response rate (cORR) evaluated by independent central review (ICR) was 41.3% (95% CI: 30.4-52.8), while Kaplan Meier curve analysis showed a median DOR of 12.9 months (95% CI: 6.0- not estimable). Previous studies have shown that the historical remission rate of BTC patients receiving second-line standard care chemotherapy is only 5-15%.
The FDA has granted breakthrough therapy designation to zanidatamab for the treatment of HER2 gene amplified BTC patients. Zanidatamab has also been granted fast track and orphan drug status by the FDA for the treatment of gastric and esophageal adenocarcinoma, and has obtained breakthrough therapy recognition in China. According to the press release, if approved, zanidatamab will become the first HER2 targeted drug approved by the FDA for the treatment of HER2 positive locally advanced or metastatic BTC patients.

Source: https://pharm.jgvogel.cn/c1457659.shtml