Annual inventory: 19 drugs were rejected by the FDA in 2022; Involving Merck, Gilead, Cinda...

New drug research and development is nine deaths, and at any stage there may be a risk of failure. If the drug cannot be successfully approved for marketing after entering the regulatory review and approval stage after the clinical trial, it will mean huge capital investment and time.

The approval of new drugs will certainly cause a high degree of excitement, but those drugs that have not been successful in one time are also worth paying attention to, and although they fail, they will bring new inspiration to successors.

According to incomplete statistics, the FDA approved a total of 37 new drugs in 2022, but at least 19 drugs were also refused, as shown in the table below. The drug rejection involves 5 rare disease drugs (Somatrogon, bardoxolone, Oleogel-S10, NurOwn and Parovastine), and the reasons for these drug rejections are nothing more than manufacturing problems, safety and efficacy need more clinical trial data to verify.

Drugs rejected by the FDA in 2022

It is worth mentioning that zandelisib and Vadadustat, which were rejected in 2022, have a far-reaching impact on the development of drugs with the same target. In recent years, the development of PI3K inhibitors and HIF-PH inhibitors has not been smooth, and these two types of drugs have not progressed smoothly due to safety of many products.

Among the 19 drugs rejected in 2022, two are domestic innovative drugs, namely sindilimab and sulfatinib, both of which have been approved for marketing in China.

In addition, some drugs rejected by the FDA have been approved in Europe or other pharmaceutical markets, such as gefapixant in Japan, Somatrogon in Japan and Europe, Oleogel-S10 in Europe...

1.Gefapixant

gefapixant is an oral, selective P2X3 receptor antagonist that inhibits extracellular ATP signaling by acting on P2X3 receptors present on airway vagal C fibers and reduces sensory nerve activation and cough.

It was approved in Japan in January 2022 for the treatment of refractory chronic cough (RCC) or unexplained chronic cough (UCC) in adults. However, the drug's NDA in the United States was rejected by the FDA, which stated in the CRL that the refusal of gefapixant had nothing to do with the drug's safety risks.

2.somatrogon

Somatrogon is a long-acting recombinant human growth hormone administered once a week that was developed to treat growth hormone deficiency (GHD) in children. In January 2022, FDA issued a full response letter (CRL) to somatrogon's BLA.

However, somatrogon is approved in Japan and the European Union for the treatment of GHD patients aged 3 years and older who develop growth disorders due to insufficient secretion of growth hormone.

3.bardoxolone

Bardoxolone is a once-daily oral Nrf2 activator. As a transcription factor, Nrf2 promotes the resolution of inflammation by restoring mitochondrial function, reducing oxidative stress, and inhibiting multiple molecular pathways such as pro-inflammatory signaling.

In April 2021, the FDA accepted bardoxolone's NDA for the treatment of Alport syndrome-related CKD, and in 2022 the FDA refused to approve the NDA on the grounds that it was consistent with the expert committee's view that it did not believe that there were data to demonstrate the safety and efficacy of bardoxolone in the field of Alport syndrome-related CKD, and requested more data from Reata Pharmaceuticals to prove it.

4.Oleogel-S10

Oleogel-S10 is made with a dry extract containing birch bark (birch bark layer), a natural substance that provides birch brain and related triterpenoids, together with sunflower oil to make an oleogel for topical administration. The drug accelerates wound healing by stimulating the migration of keratinocytes and promoting differentiation into mature epithelial skin cells.

In February 2022, Amryt Pharmaceuticals announced that it received an FDA-issued CRL for Oleogel-S10 for the treatment of atrophic and functional epidermolysis bullosa (EB) skin symptoms. The FDA asked Amryt to submit more confirmatory evidence demonstrating the effectiveness of Oleogel-S10 in EB treatment.

5.Lenacapavir

Lenacapavir is a capsid inhibitor that inhibits HIV-1 replication primarily by interfering with multiple important steps of the viral life cycle, involving capsid-mediated uptake of HIV-1 proviral DNA, viral assembly and release, and capsid core formation.

In March 2022, the FDA issued a CRL in response to the lenacapavir marketing application. In the CRL, the FDA points to chemical manufacturing control (CMC) issues related to the compatibility of lenacapavir injection with the proposed glass vial.

However, in December last year, the FDA approved the drug for the treatment of severely pretreated HIV-1 patients who have failed current antiretroviral treatment regimens, becoming the only HIV treatment drug approved for marketing twice a year.

6.zandelisib

zandelisib is an oral phosphatidylinositol 3-kinase (PI3K) δ inhibitor. In March 2022, MEIPharma announced that the FDA refused to approve zandelisib for the treatment of relapsed or refractory follicular lymphoma.

The FDA says a randomized trial is needed to fully evaluate the efficacy and safety of PI3K inhibitor candidates, including zandelisib.

Based on this view, FDA discourages submissions based on Phase 2 TIDAL study data and emphasizes that the Company will continue to conduct the ongoing, randomized Phase 3 COASTAL study as planned.

7. Cindilimab

Cindilimab is a PD-1 monoclonal antibody developed by Innovent Biologics and has been approved for multiple indications in China.

In February 2022, the FDA held an ODAC meeting on whether the Sintilimab ORIENT-11 trial was suitable for the United States, and the final committee voted 14 in favor and 1 against to ask Innovent/Eli Lilly to provide additional data to prove the utility of its PD-1 monoclonal antibody in the US population.

In March 2022, Innovent announced that the FDA refused to approve sindilimab in combination with pemetrexed and platinum-based chemotherapy for first-line treatment in patients with non-squamous NSCLC. In its response letter, the FDA recommended that sindi monoclonal antibody in combination with chemotherapy and standard therapy for first-line metastatic NSCLC be conducted in multi-regional, non-inferiority clinical trials with overall survival as the endpoint.

8.Vadadustat

vadadustat is an oral hypoxia-inducible factor aminoyl hydroxylase (HIF-PH) inhibitor used in adults to treat anemia associated with chronic kidney disease (CKD).

In March 2022, Akebia announced that it had received a full response letter (CRL) from the FDA regarding the vadadustat New Drug Application (NDA). The FDA said the data in the NDA do not support the beneficial benefit of vadadustat for dialysis and non-dialysis patients — risk assessment. The FDA also expressed safety concerns, noting that the drug did not achieve the non-inferiority of MACE (major adverse cardiovascular events) in non-dialysis patients, increased the risk of thromboembolic events due to vascular access thrombosis in dialysis patients, and increased risk of drug-induced liver injury.

9. Sulfatinib

Sulfatinib is an oral tyrosine kinase inhibitor that was approved in China in December 2020 for the treatment of advanced non-pancreatic neuroendocrine tumors, and in June 2021 for the treatment of advanced pancreatic neuroendocrine tumors.

In April 2022, Hutchison announced that it had received a full response letter from the FDA that concluded that the current data package based on two successful China Phase III studies and one U.S. bridging study is not sufficient to support the current approval of the drug in the United States, and that more international multicenter clinical trials (MRCTs) representing the US patient population are needed to support the approval of the drug in the United States.

10.VP-102

VP-102 is a proprietary drug-device combination product, administered by topical application, for the treatment of molluscum contagiosum, its active pharmaceutical ingredient cantharidin is the active ingredient of the insect animal Cantharid, is a naturally occurring skin foaming agent, which can lead to the degradation of desmosomes, a unique intercellular adhesion structure unique to epithelial cells, exerting cell-to-cell connectivity.

In May 2022, the FDA refused to approve VP-102 because Sterling Pharmaceuticals Services, the contract manufacturer that manufactured the drug, found a defect during a routine review, which led to Official Action Instruction (OAI) status.

11.Bimekizumab

Bimekizumab is an IL-17A/IL-17F inhibitor approved by the European Union in August 2021 for the treatment of adult patients with moderate to severe plaque psoriasis suitable for systemic therapy.

In May 2022, the FDA rejected Bimekizumab. The CRL states that "certain pre-approval review actions must be resolved before the application is approved".

12. Atitidil

Atitidil is a biologically active and abundant human in vivo peptide that acts as a ligand for specific transmembrane G protein-coupled receptors (VPAC1, VPAC2 and PACAP-R1) and is one of the signaling molecules of the neuroendocrine immune network, with antiproliferative, anti-inflammatory and immunomodulatory properties. In a variety of animal models of respiratory distress, acute lung injury, and inflammation, Ateptidil has shown potent anticytokine activity.

In July 2022, NRxPharmaceuticals announced that the FDA refused to grant aviptadil (Zyesami) an Emergency Use Authorization (EUA) for the treatment of patients at risk of direct death from respiratory failure.

It is worth mentioning that this is the second EUA for alpisidil to be rejected by the FDA, which rejected the request in November 2021 citing lack of efficacy and safety data.

13.Pimavanserin

pimavanserin, a selective serotonin (5-HT) reverse agonist and antagonist that preferentially targets the 5-HT2A receptor, was approved by the FDA in April 2016 for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis (PDP).

In August 2022, Acadiaia announced that the FDA issued a full response letter (CRL) to the Supplemental New Drug Application (sNDA) for the treatment of hallucinations and delusions associated with Alzheimer's psychiatric delusions.

The CRL content indicates that the FDA believes that current data based on the Study019 and Study045 trials are insufficient to support the approval of pimavanserin in the United States, and recommends that Acadiaia add additional trials for ADP.

The FDA said the Study019 study achieved a statistically significant therapeutic effect at the primary endpoint, but they believe there are limitations to the interpretability of the findings.

In addition, the FDA said that the positive treatment effect of pimavanserin on dementia-related psychosis (DRP) in the Study045 trial is equally untrustworthy, because 50% of PDP patients have dementia, and the treatment effect of PDP dementia subgroup in the study was also very positive.

14.Roluperidone

Roluperidone is a 5-HT2A receptor and σ2 receptor antagonist originally developed by MitsubishiTanabe.

In August 2007, Minerva Neurosciences entered into a license agreement with MitsubishiTanabe to acquire exclusive development and commercialization rights for roluperidone in Asian countries other than China, Japan, India and South Korea.

In October 2022, MinervaNeurosciences announced that it received a CRL from the FDA for the treatment of roluperidone NDA for the treatment of negative symptoms in schizophrenia. The FDA said Minerva could hold typeA meetings to discuss the contents of the CRL.

15.Hepcludex

Hepcludex, a first-in-class therapy for HDV that blocks the virus from entering liver cells by binding to NTCP receptors, was conditionally approved by the European Medicines Agency (EMA) in July 2020 for the treatment of adult patients with compensated chronic HDV infection.

In October 2022, Gilead disclosed in its third quarter 2022 earnings report that it had received a CRL from the FDA, and revealed that it was because the FDA was concerned about the production and delivery of Hepcludex (bulevirtide).

16.Poziotinib

Poziotinib is a HER2 exon 20 insertion mutation tyrosine kinase inhibitor (TKI), developed by Korean Korean Pharmaceuticals. Due to its unique structure, Poziotinib has been shown in preclinical experiments to irreversibly bind to HER2 receptors carrying exon 20 insertion mutations, inhibiting its function and kinase activity, thereby inhibiting cancer cell proliferation, leading to cancer cell death.

In September 2022, the FDA's Oncology Drug Advisory Committee (ODAC) voted 9-4 to conclude that poziotinib's current benefits do not outweigh its risks. The FDA said that the problems with positinib are first, low ORR and short DOR; Second, the safety of the recommended dose is poor; Third, dose optimization is insufficient, and confirmatory clinical trials have not recruited patients.

In November 2022, Spectrum Pharmaceuticals announced that it had received a full response letter (CRL) from the FDA regarding the New Drug Application (NDA) of poziotinib (positinib). CRL requires that Spectrum require additional data, including randomized controlled clinical studies, to be approved for this indication.

17.NurOwn

NurOwn is an innovative autologous cell therapy developed by Brainstorm that uses bone marrow-derived mesenchymal stem cells to be expanded and differentiated in vitro and cultured under patented conditions to induce these cells to secrete high levels of neurotrophic factors to become MSC-NTF cells.

Autologous MSC-NTF cells can efficiently deliver a variety of neurotrophic and immunomodulatory cytokines directly to the site of injury, which play an important role in slowing or stabilizing disease progression. In November 2020, BrainstormCellTherapeutics announced that the FDA had rejected NurOwn for the treatment of muscle ALS.

18. Parovatamine

Parovatine is an orally available selective retinoic acid receptor γ (RARγ) agonist developed by Clementia (Roche subsidiary), which inhibits the abnormal activation of its downstream pathway by acting on the bone morphogenetic protein (BMP) type I receptor ACVR1/ALK2 (ACVR1/ALK2 mutation is the pathogenic mechanism of OF), thereby inhibiting HO.

In April 2019, Ipsen acquired Clementia for US$1.31 billion, acquiring a global interest in parovatamine. In December 2022, Ipsen announced that it had received a full response letter (CRL) from the FDA regarding the New Drug Application (NDA) for parovastatine for the treatment of progressive muscular ossification (FOP). FDA requires Ipsen to submit additional clinical trial data in the CRL that are not related to efficacy and safety.

19.Omburtamab

Omburtamab is a radionuclide iodine-131-labeled monoclonal antibody targeting B7-H3, targeting B7-H3-expressing cells in a variety of solid tumors such as neuroblastoma, and binding to FG ring-dependent conformation, a key region of biological function on the B7-H3 molecule.

In December 2022, Y-mAbsTherapeutics received a CRL issued by the FDA for omburtamab for the treatment of leptomeningeal metastases in central nervous system/neuroblastoma.

At a previous ODAC meeting, reviewers voted 16Vs0 that there was not enough evidence that omburtamab improved overall survival. FDA recommends that Y-mAbs meet with FDA to fully discuss well-controlled trial designs to provide substantial evidence of efficacy and risk-benefit.

summary

An FDA rejection does not mean that the development of these drugs is unsuccessful, and some of them still have the possibility of becoming blockbusters, such as Evaluate's forecast that bardoxolone sales will reach $1.12 billion in 2024, and Unisby Bimekizumab's sales are expected to reach $1.63 billion in 2026. It is expected that these drugs can eventually obtain FDA regulatory approval in the future, bringing more possibilities.