Trodelvy Archives - European Industrial Pharmacists Group (EIPG)

The EU Parliament voted its position on the Unitary SPC

by Giuliana Miglierini The intersecting pathways of revision of the pharmaceutical and intellectual property legislations recently marked the adoption of the EU Parliament’s position on the new unitary Supplementary Protection Certificate (SPC) system, parallel to the recast of the current Read more

Reform of pharma legislation: the debate on regulatory data protection

by Giuliana Miglierini As the definition of the final contents of many new pieces of the overall revision of the pharmaceutical legislation is approaching, many voices commented the possible impact the new scheme for regulatory data protection (RDP) may have Read more

Environmental sustainability: the EIPG perspective

Piero Iamartino Although the impact of medicines on the environment has been highlighted since the 70s of the last century with the emergence of the first reports of pollution in surface waters, it is only since the beginning of the Read more

Approvals and flops in drug development in 2023

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by Giuliana Miglierini

Approvals and flops in drug development in 2023

The European Medicines Agency published its annual highlights, showing 77 medicines were recommended for marketing authorisation, and just 3 received a negative opinion (withdrawals were 19).

In 2023 some highly expected candidates under clinical development failed to meet the fixed endpoints, as reported by Fierce Biotech. The impact of the Covid-19 pandemic reduced the commercial performance of medical products launched in 2020, highlights the Trinity Annual Drug Index. We summarise the main features emerging from the three documents.

The approval of the first CRISPR/Cas-9 gene therapy

The only advanced therapy medicinal product (ATMP) recommended by EMA in 2023 represents a true innovation in the therapeutic arsenal to treat transfusion-dependent beta-thalassemia and severe sickle cell disease. Casgevy (exagamglogene autotemcel) is the first-in-class CRISPR/Cas 9 gene therapy approved, targeting specific mutations in the genome of patients that affect the production or function of haemoglobin.

EMA recommended in 2023 39 medicines based on a new active substance never authorised before in the EU. Generics and biosimilars were about a third of the approved products (14 and 8, respectively). On the other hand, 17 products received an orphan designation. Other new medicinal products followed different dedicated regulatory pathways, such as Prime (3) or accelerated assessment (3). One product received approval under exceptional circumstances, other 8 a conditional marketing authorisation.

Oncology continues to represent the most attractive therapeutic area for pharmaceutical R&D, with a total of 14 new medicinal products.

Elrexfio (elranatamab) and Talvey (talquetamab) were approved for the treatment of adult patients with relapsed or refractory multiple myeloma, a rare cancer of the bone marrow that affects plasma cells. Two other new medicines – Columvi (glofitamab) and Tepkinly (epcoritamab) – were approved for the treatment of diffuse large B-cell lymphoma, an aggressive cancer of the lymphatic system. The treatment of myelofibrosis, a rare blood cancer that affects the bone marrow, can benefit from the approval of Omjjara (momelotinib). Cerebral glioma in paediatric patients from one year of age is the target of the combination of Finlee (dabrafenib) and Spexotras (trametinib).

Among other particularly innovative products recommended for approval by EMA are two vaccines to protect against lower respiratory tract disease caused by respiratory syncytial virus, Abrysvo (bivalent, recombinant) targeting small infants via immunisation of the mother during pregnancy (and over-60 adults), and Arexvy (recombinant, adjuvanted), representing the first vaccine for active immunisation of adults aged 60 years and older.

EMA also recommended two medicines for use in countries outside the EU, under the regulatory procedure “EU-Medicines for all” (EU-M4All). Arpraziquantel (arpraziquantel) targets schistosomiasis, a neglected tropical disease caused by parasitic trematode worms and affecting an estimate of 50 million young children. Fexinidazole Winthrop (fexinidazole) is already in use from 2018 to treat human African trypanosomiasis, a disease caused by the parasite trypanosoma brucei gambiense and also known as sleeping sickness. The CHMP extended the indications to include treatment of the more acute and lethal form of the disease caused by trypanosoma rhodesiense.

The main failures in clinical R&D

Pharmaceutical R&D may also lead to failure of the clinical development for candidate products. A selection of the more significant flops in 2023 as for clinical trials has been published by Fierce Biotech on its website.

An already FDA approved gene therapy product is also included in the list, Sarepta’s Elevidy for the treatment of Duchenne muscular dystrophy, as its phase 3 Embark study didn’t meet the primary endpoint. The product is now under further scrutiny by the FDA. As for vaccines, a major failure refers to Janssen Pharmaceuticals’ HIV vaccine and its phase 3 Mosacio study, that was terminated as it was not expected to meet the primary endpoint. According to Fierce Biotech, Johnson & Johnson would have ended the development of the HIV vacci-ne and completely revised the infectious disease R&D unit. Failure to meet the expected benefit (3.5-month overall survival) in the phase 3 Sapphire trial impacted also sitravatinib, a spectrum-selective kinase inhibitor developed by Mirati Therapeutics to overcome resistance to checkpoint inhibitors in the treatment of non-small lung cell carcinoma. Tarcocimab tedromer is an anti-VEGF antibody biopolymer conjugate developed by Kodiak Sciences to treat diabetic macular edema, and that did not meet the primary endpoint in a phase 3 trial compared to the approved therapy. The same occurred to evobrutinib, a BTK inhibitor from Merck KGaA to treat multiple sclerosis, that failed the comparison with the reference product in two phase 3 studies. The failure of the potential blockbuster factor-XIa inhibitor asundexian, developed by Bayer for treatment of atrial fibrillation with stroke risk, was due to an observed “inferior efficacy” com-pared to the standard treatment Eliquis. The failure of efruxifermin (a FGF21 analog) in a phase 2b study aimed to treat fibrosis in cirrhotic MASH patients was attributed by Akero Therapeutics to the fact enrolled patients may have reached a too advanced state of disease for the treatment to be effective. The failure of Nektar Therapeutics’ phase 2 clinical trial in lupus with Rezpeg (rezpegaldesleukin) is a less typical occurrence, as it was due to errors made by the industrial partner Eli Lilly in the analysis of data from a phase 1b trial in eczema and psoriasis. Lilly admitted the errors and was then sued by Nektar.

The land of unicorns also crashed down when izokibep, a small protein developed by Acelyrin, failed the primary endpoint against placebo. The company had received a $540 million IPO, to then see its shares value decreasing by 58%. The failure was attributed to a programming error by a CRO, which according to Fierce Biotech is under investigation by the sponsor. The potential of artificial intelligence in supporting drug discovery may also be impacted by the failure of BEN-2293, a topical pan-Trk inhibitor in eczema developed by Benevolent AI which failed to meet the secondary endpoints of the safety-focused study.

The commercial performance of products approved in 2020

The commercial performances of novel drugs approved in 2020 are the focus of the Trinity Annual Drug Index.

Oncology represented in 2020 the leading indication (29% of the total 58 unique FDA drug and biologic approvals), followed by neurology (16%). The combination of the two therapeutic areas marked a net increase compared to 2017 (45% vs 34%, respectively). Half (9/17) of the new pro-ducts approved in Oncology were small molecules, mainly mutation directed. A quarter (24%) of the new medicines were monoclonal antibodies. The antibody drug conjugates Trodelvy, in particular, was the highest performing Oncology drug overall.

The strong impact of the Covid-19 pandemic on the pharmaceutical industry in 2020, with many shifts of priorities in development and the need to manage shortages and disruptions of the supply chain, led to a lower commercial performance of the new products launched com-pared to 2016-2019. Good commercial results were obtained only by new medicines addressing significant unmet need or providing very strong therapeutic benefits.

The Trinity Annual Drug Index also highlights that approx. 21% (12/58) of approved products in 2020 constituted a “first launch” for their respective companies. None of them surpassed their forecast expectations, and approx. a half significantly underperformed.