Searching for a vaccine and a drug in the surreal and accelerated world of Covid-19 research

What Is the World Doing to Create a COVID-19 Vaccine?

Building the critical path for COVID-19 therapeutics

How to Discover Antiviral Drugs Quickly

The world needs Covid-19 vaccines. It may also be overestimating their power

From CFR:

Public officials worldwide have stressed that the pandemic likely will not end until there is an effective vaccine. Even after a vaccine is approved, however, there remains the tremendous challenge of producing enough of it for the world’s population. An estimated one billion doses would need to be manufactured just to vaccinate workers in health care and other essential industries globally, and that is if only a single dose is required for each person.
This task has both motivated countries to prepare for large-scale production, as well as pitted them against one another amid fears of a potentially limited vaccine supply. While Brazil, China, and India all have large vaccine industries, they also have among the largest populations, and they could reserve their vaccine supplies for their own citizens before opening them up to others. Some countries are seeking to strike monopoly agreements with vaccine manufacturers to avoid domestic shortages. Experts including CFR’s Bollyky have warned that bidding wars over a vaccine will lead to inequitable distribution and, ultimately, fail to eliminate the risk of new outbreaks.
Moreover, amid these extraordinary efforts to secure a vaccine, scientists are still investigating how this new coronavirus behaves and trying to answer the many questions people have about the risk it poses and how protected they will be. This includes how effective a vaccine will be against a mutating coronavirus, though researchers point out that mutations do not necessarily mean different strains of the virus or changes in its infectiousness or lethality. Uncovering such details about the virus, they say, will only help in the development of a successful vaccine.

From NEJM:

 So, what is happening now? The laborious, decade-long, classic pathway for the discovery and approval of new drugs could hardly be less well suited to the present pandemic. Repurposing existing drugs offers a potentially rapid mechanism to deployment, since the safety profiles are known. Therefore, a preliminary report of a supercomputer-driven ensemble docking study of a repurposing compound database to the viral S protein was published on a preprint server in mid-February, with 8000 compounds ranked according to the calculated binding affinity to the receptor-binding domain of the S protein.3 Top-ranked compounds from the original S-protein virtual screen are being tested for activity against the live virus. The results will inform future calculations in a speedy, iterative process.

Patents are Not the Problem (right now)!

 I agree absolutely with Alex Tabarrock and his post in Marginal revolution. He says:

Patents are not the problem. All of the vaccine manufacturers are trying to increase supply as quickly as possible. Billions of doses are being produced–more than ever before in the history of the world. Licenses are widely available. AstraZeneca have licensed their vaccine for production with manufactures around the world, including in India, Brazil, Mexico, Argentina, China and South Africa. J&J’s vaccine has been licensed for production by multiple firms in the United States as well as with firms in Spain, South Africa and France. Sputnik has been licensed for production by firms in India, China, South Korea, Brazil and pending EMA approval with firms in Germany and France. Sinopharm has been licensed in the UAE, Egypt and Bangladesh. Novavax has licensed its vaccine for production in South Korea, India, and Japan and it is desperate to find other licensees but technology transfer isn’t easy and there are limited supplies of raw materials:

Virtually overnight, [Novavax] set up a network of outside manufacturers more ambitious than one outside executive said he’s ever seen, but they struggled at times to transfer their technology there amid pandemic travel restrictions. They were kicked out of one factory by the same government that’s bankrolled their effort. Competing with larger competitors, they’ve found themselves short on raw materials as diverse as Chilean tree bark and bioreactor bags. They signed a deal with India’s Serum Institute to produce many of their COVAX doses but now face the realistic chance that even when Serum gets to full capacity — and they are behind — India’s government, dealing with the world’s worst active outbreak, won’t let the shots leave the country.

Plastic bags are a bigger bottleneck than patents. The US embargo on vaccine supplies to India was precisely that the Biden administration used the DPA to prioritize things like bioreactor bags and filters to US suppliers and that meant that India’s Serum Institute was having trouble getting its production lines ready for Novavax. CureVac, another potential mRNA vaccine, is also finding it difficult to find supplies due to US restrictions (which means supplies are short everywhere). As Derek Lowe said:

Abolishing patents will not provide more shaker bags or more Chilean tree bark, nor provide more of the key filtration materials needed for production. These processes have a lot of potential choke points and rate-limiting steps in them, and there is no wand that will wave that complexity away.

Technology transfer has been difficult for AstraZeneca–which is one reason they have had production difficulties–and their vaccine uses relatively well understood technology. The mRNA technology is new and has never before been used to produce at scale. Pfizer and Moderna had to build factories and distribution systems from scratch. There are no mRNA factories idling on the sidelines. If there were, Moderna or Pfizer would be happy to license since they are producing in their own factories 24 hours a day, seven days a week (monopolies restrict supply, remember?). Why do you think China hasn’t yet produced an mRNA vaccine? Hint: it isn’t fear about violating IP. Moreover, even Moderna and Pfizer don’t yet fully understand their production technology, they are learning by doing every single day. Moderna has said that they won’t enforce their patents during the pandemic but no one has stepped up to produce because no one else can.

 More information in his post.

Some weeks ago a journalist asked to me the same question, and I said more or less, the same!. There is no need to start discussions about patents in WCO, only the enforcement and implementation of mandatory licenses can be helpful.

¿Qué opina sobre las patentes de las vacunas de la covid-19? ¿Considera que, en este caso, deberían contemplarse excepciones al derecho de explotación exclusiva?

Antes de hablar de patentes, conviene considerar la inversión pública en investigación. Por ejemplo, en la medida que hay una vacuna cuyo coste de investigación ha sido sufragado en un 97% por el sector público, resulta lógico que se compre a un precio equivalente al coste de fabricación, tal como sucede.  Ahora bien, también sería deseable que se obligara a licenciar el proceso a otros fabricantes. En el caso de vacunas de RNA mensajero, el nivel de inversión pública en Estados Unidos es notable y sin embargo no ha sucedido lo mismo. Por consiguiente, los gobiernos deben gestionar las contrapartidas de la inversión pública en investigación.

•  ¿Considera que sería positiva una liberación de las patentes de las vacunas contra la covid? ¿Por qué? 

En mi opinión ya existen mecanismos que permiten conseguir que las vacunas sean asequibles y son las licencias obligatorias. Tal regulación que se configuró en la reunión de la OMC en Doha en el año 2003. Desafortunadamente no se ha desarrollado suficientemente por los países. Las condiciones por las que se deberían aplicar tales licencias quedan explícitas en la Declaración. Tales condiciones hacen referencia a la definición de emergencia y crisis de salud pública. En esta pandemia se daban las condiciones para su aplicación. Visto así, el debate necesita centrarse entre patentes y licencias obligatorias atendiendo a condiciones concretas. 

•  ¿Existen mecanismos ya reglados para que, en situaciones como ésta, más allá de la patente, se garantice la llegada de las vacunas a todos los países (incluyendo los de nivel económico más bajo)?

En realidad la Alianza Mundial para vacunas e inmunización (GAVI) nació para ello. En el caso de la COVID, la OMS a través de GAVI y otras instituciones ha impulsado la iniciativa COVAX que pretende ofrecer vacunas a países en desarrollo. Aún así sabemos que el esfuerzo es insuficiente a la vista de los resultados, el 87% de las vacunas ha ido a países ricos, y en los menos desarrollados tan solo ha llegado el 0,2%.

 

Vaccine allocation (2)

 An ethical framework for global vaccine allocation

Ezequiel Emanuel et al. article:

Fairly distributing a COVID-19 vaccine among countries is a problem of distributive justice. Although governments will be the initial recipients of vaccine, fair distribution across countries must reflect a moral concern for the ultimate recipients: individuals. Three values are particularly relevant: benefiting people and limiting harm, prioritizing the disadvantaged, and equal moral concern.

Benefiting people and limiting harm is widely recognized as important across ethical theories. Realizing this value requires defining relevant benefits, measuring them, and assessing the relative urgency—the importance and time sensitivity—of countries’ needs. A successful vaccine produces direct benefits by protecting people against death and morbidity caused by infection. It also produces indirect benefits by reducing death and morbidity arising from health systems overstressed by the pandemic, and by reducing poverty and social hardship such as closed schools.

Prioritizing the disadvantaged is a fundamental value in ethics and global health (10, 11). Realizing this value requires that vaccine distribution reflect special concern for people who are disadvantaged. Fairly distributing a COVID-19 vaccine internationally therefore requires assessing different types of disadvantage. Are the worst-off countries those experiencing the greatest poverty? Those where people have the lowest life expectancies?

Equal moral concern requires treating similar individuals similarly and not discriminating on the basis of morally irrelevant differences, such as sex, race, and religion. Distributing different quantities of vaccine to different countries is not discriminatory if it effectively benefits people while prioritizing the disadvantaged.

And the allocation model: 

 The Fair Priority Model proceeds in three phases, preventing more urgent harms earlier (see the Table). Phase 1 aims at reducing premature deaths and other irreversible direct and indirect health impacts. Phase 2 continues to address enduring health harms but additionally aims at reducing serious economic and social deprivations such as the closure of nonessential businesses and schools. Restoring these activities will lower unemployment, reduce poverty, and improve health. Finally, phase 3 aims at reducing community transmission, which in turn reduces spread among countries and permits the restoration of prepandemic freedoms and economic and social activities.

 

Vaccine diplomacy

 PREVENTING THE NEXT PANDEMIC. Vaccine Diplomacy in a Time of Anti-science

Throughout modern history, vaccines have surpassed all other biotechnologies in terms of their impact on global public health. Because of vaccines, smallpox was eradicated, and polio has been driven to near global elimination, while measles deaths have declined more than 90%, and Haemophilus influenzae type b meningitis is now a disease of the past in the United States and elsewhere.

I define one part of vaccine diplomacy as a subset or specific aspect of global health diplomacy in which large-scale vaccine delivery is employed as a humanitarian intervention, often led by one or more of the UN agencies, most notably Gavi, UNICEF, and WHO, or potentially a nongovernmental development organization

 Do vaccines really deserve their own designation for a special type of diplomacy? Yes, I believe so, especially when we consider that between the past century and this one vaccines have saved hundreds of millions of lives [2]. In this sense, the technology of vaccines and their widespread delivery represent our most potent counterforce to war and political instability in modern times. Vaccines represent not only life-saving technologies and unparalleled instruments for reducing human suffering, but they also serve as potent vehicles for promoting international peace and prosperity. They are humankind’s single greatest invention.

The greater issue is that in each of these four cases—smallpox, polio, Ebola, and COVID-19—the global health community had to respond to a crisis and scramble to rapidly develop, test, license, and distribute these vaccines. Could we also implement an anticipatory system in which nations prioritize vaccine diplomacy and routinely employ it to improve international relations? The Global Health Security Agenda does not currently emphasize vaccine development, although new organizations like CEPI and start-up innovation funds from the Japanese and South Korean governments represent promising steps toward global vaccine diplomacy. I am an enthusiastic champion of their efforts. However, I also believe that an opportunity exists for a more comprehensive effort to tackle the world’s most prevalent poverty-related neglected diseases while simultaneously expanding international scientific cooperation as a core element.

The answer might be found somewhere in the G20...

 

Covid vaccine landscape

 Evolution of the COVID-19 vaccine development landscape

Currently there are 321 vaccine candidates for COVID, however only 33 have entered clinical trials.

Although the leading COVID-19 vaccine candidates have progressed to advanced stages of clinical development at exceptional speed, many uncertainties remain given the lack of robust clinical data so far. Moreover, given the highly unusual circumstances associated with developing a vaccine during the evolution of a novel global pandemic, probability of success benchmarks for traditional vaccine development are likely to underrepresent the risks associated with delivering a licensed vaccine for COVID-19. The most advanced candidates are expected to begin reporting data from pivotal studies over the coming months, which if positive will be used to support accelerated licensure of the first COVID-19 vaccines. 

 

Prioritising the vaccine

 Framework for Equitable Allocation of COVID-19 Vaccine

Health equity is intertwined with the impact of COVID-19 and there are certain populations that are at increased risk of severe illness or death from COVID-19. In the United States and worldwide, the pandemic is having a disproportionate impact on people who are already disadvantaged by virtue of their race and ethnicity, age, health status, residence, occupation, socioeconomic condition, or other contributing factors.

Framework for Equitable Allocation of COVID-19 Vaccine offers an overarching framework for vaccine allocation to assist policy makers in the domestic and global health communities. Built on widely accepted foundational principles and recognizing the distinctive characteristics of COVID-19, this report's recommendations address the commitments needed to implement equitable allocation policies for COVID-19 vaccine.

If vaccines are coming in the next months and we all agree that supply will not fulfill demand, then we need to prioritise. This publication of the National Academy of Medicine provides some usegul insights. However, the most important is to have a concrete application in specific contexts.

Joana Biarnés

Vaccine nationalism (2)

 Designing Pull Funding For A COVID-19 Vaccine

If somebody wants to avoid vaccine nationalism, then there is a need for a global mechanism of allocation. You'll find a specific proposal in Health Affairs about this issue. Unfortunately, it seems that nobody cares about its application.

In baseline simulations, the optimal pull program spends an average of $50 per dose to obtain an average of 2.2 billion doses—$110.4 billion in total. The size of our pull program is driven by the enormous estimated benefit from COVID-19 vaccination, leading the optimal program to induce nearly all firms to participate (average of 9.8 out of 10), installing nearly all  available capacity, and allowing more people to be vaccinated with less delay. To secure this level of participation requires the award to cover all but the most exorbitant cost draws. On average, 2.9 of the 10 candidate firms develop a successful vaccine, generating a social benefit (net of program costs) of $2.8 trillion.

 Our mechanism offers two advantages over the free market. First, it dramatically lowers cost—by a factor of thirteen—by averting a bidding war. Given our program’s larger size compared with other policy proposals, it is ironic that its advantage would be to lower costs compared with the private market. Second, it allows for more efficient allocation, moving some vulnerable people in lowerincome countries up in the queue ahead of some from richer countries experiencing lower harm. A conjectured third benefit of our mechanism— enhancing investment in more candidates and more capacity—did not materialize in baseline simulations. Demand for a COVID-19 vaccine is so high that every firm in every simulation finds investing profitable under a free-market scenario. This third benefit does materialize in scenarios with substantially more per firm capacity than in the baseline.

 Eivissa, Francesc Català i Roca

 

Vaccines for all

How to Develop a COVID-19 Vaccine for All

Messages from Mazzucato and Torreele:

The first, critical step is to adopt a mission-oriented approach that focuses both public and private investments on achieving a clearly defined common goal: developing an effective COVID-19 vaccine(s) that can be produced at global scale rapidly and made universally available for free. Realizing this aim will require firm rules regarding intellectual property (IP), pricing, and manufacturing, designed and enforced in ways that value international collaboration and solidarity, rather than competition between countries.

Second, to maximize the impact on public health, the innovation ecosystem must be steered to use collective intelligence to accelerate advances. Science and medical innovation thrives and progresses when researchers exchange and share knowledge openly, enabling them to build upon one another’s successes and failures in real time.

Third, countries must take the lead in building and buttressing manufacturingcapabilities, particularly in the developing world. While an effective COVID-19 vaccine probably will not be available for another 12-18 months, a concerted effort is needed now to put in place the public and private capacity and infrastructure needed to produce rapidly the billions of doses that will be required.

Because we don’t know yet which vaccine will prove most effective, we may need to invest in a range of assets and technologies. This poses a technological and financial risk that can be overcome only with the help of entrepreneurial states backed by collective, public-interest-driven financing, such as from national and regional development banks, the World Bank, and philanthropic foundations.

Finally, conditions for ensuring global, equitable, and affordable access must be built into any vaccine-development program from the start. This would allow public investments to be structured less like a handout or simple market-fixer, and more like a proactive market-shaper, driven by public objectives.

PS. Masks, tests, treatments, vaccines – why we need a global approach to fighting Covid-19 now
Bill Gates dixit:

 I’m a big believer in capitalism – but some markets simply don’t function properly in a pandemic, and the market for lifesaving supplies is an obvious example. The private sector has an important role to play, but if our strategy for fighting Covid-19 devolves into a bidding war among countries, this disease will kill many more people than it has to.

Edward Hopper. Cape Cod Morning, 1950. Smithsonian American Art Museum

Els medicaments que venen i els que ja s'han aprovat el 2023

És bo fer una ullada a quins són els medicaments que previsiblement s'aprovaran l'any 2024, i els de Nature diuen que són aquests:

Medicaments per aprovar el 2024

Biologic name	Sponsor	Properties	Indication	Timing
Zolbetuximab	Astellas	Claudin 18.2-targeted mAb	Gastric cancer	January
Lifileucel	Iovance	Tumour-infiltrating lymphocyte therapy	Melanoma	February
Resmetiroma	Madrigal/Synta	Thyroid hormone receptor β agonist	NASH	March
Sotatercepta	Merck & Co./Acceleron	Fusion protein ligand trap for TGF-β superfamily	PAH	March
mRNA-1345a	Moderna	mRNA-based vaccine	RSV prevention	April
Donanemaba	Eli Lilly	Amyloid-β-targeted mAb	Alzheimer disease	Q1
EB-101a	Abeona	Gene therapy with COL7A2 transgene	RDEB	May
Patritumab deruxtecana	Merck & Co.	HER3-targeted ADC	NSCLC	June
Imetelstat	Geron	Telomerase inhibitor	Transfusion-dependent anaemia with MDS	June
Tarlatamaba	Amgen	DLL3 × CD3 T-cell engager antibody	SCLC	June
Fidanacogene elaparvoveca	Pfizer/Spark	AAV-based gene therapy with factor IX transgene	Hemophilia B	Q2
Bentracimaba	Laboratoires SERB	Ticagrelor-neutralizing antibody	Drug toxicity	1H
Crovalimaba	Roche	C5-targeted mAb	PNH	July
Danicopana	AstraZeneca/Alexion	Factor D inhibitor	PNH	July
Midomafetaminea	MAPS	MDMA	PTSD	August
Xanomeline plus trospium	Karuna/BMS	Muscarinic receptor modulators	Schizophrenia	September
Acoramidis	BridgeBio	TTR stabilizer	TTR amyloidosis	December
Marstacimab	Pfizer	TFPI-targeted mAb	Haemophilia A and B	Q4
Afamitresgene autoleucela	Adaptimmune	MAGE-A4-targeted autologous, engineered T cell therapy	Synovial sarcoma	2024

aBreakthrough designated drug. AAV, adeno-associated virus; ADC, antibody–drug conjugate; mAb, monoclonal antibody; MDS, myelodysplastic syndromes; NASH, non-alcoholic steatohepatitis; NSCLC, non-small-cell lung cancer; PAH, pulmonary arterial hypertension; PNH, paroxysmal nocturnal haemoglobinuria; PTSD, post-traumatic stress disorder; RDEB, recessive dystrophic epidermolysis bullosa; RSV, respiratory syncytial virus; SCLC, small-cell lung cancer; TFPI, tissue factor pathway inhibitor; TTR, transthyretin. Source: BioMedTracker and press releases.

També és bo de veure què ha passat amb l'aprovació de medicaments per la FDA el 2023 i resulta que s'ha arribat a 55 nous medicaments, una xifra considerable si observem el que passava els anys anteriors, només superada el 2018

Fig. 1 | 30 years of novel FDA approvals. Annual numbers of new molecular entities (NMEs) and biologics license applications (BLAs) approved by the FDA’s Center for Drug Evaluation and Research (CDER). See Table 1 for new approvals in 2023. Products approved by the Center for Biologics Evaluation and Research (CBER), including vaccines and gene therapies, are not included in this drug count (Table 2). Source: FDA.

Fig. 2 | CDER approvals by therapeutic area. Indications that span multiple therapeutic areas are classified under only one, based on which FDA office and division reviewed the approval application. Sources: Nature Reviews Drug Discovery, FDA.

Fig. 3 | CDER approvals by modality. Small molecules, including peptides of up to 40 amino acids in length, and oligonucleotides are approved as new molecular entities (NMEs). Protein-based candidates are approved through biologics license applications (BLAs). mAb, monoclonal antibody; siRNA, small interfering RNA. Source: Nature Reviews Drug Discovery.

I la notícia de l'any ha estat CRISPR:

Vertex and CRISPR Therapeutics’ exagamglogene autotemcel (exa-cel; Casgevy) especially is the first CRISPR–Cas9-based gene editor to secure a green light from the FDA, winning an approval for sickle cell disease (SCD). Exa-cel is an ex vivo gene-edited cell therapy: blood cells are harvested from patients, genetically modified at the BCL11a transcription factor to re-enable fetal haemoglobin production, and then re-infused into patients. The therapeutically upregulated fetal haemoglobin compensates for the defects in β-haemoglobin that cause the diseases. Clinical data shows that the gene therapy has curative potential, although longer-term data are needed to assess the durability of the effect.

When Harvard Medical School and HHMI’s Stuart Orkin and colleagues discovered the role of BCL11a in fetal haemoglobin production in 2008, it was unclear how to drug the transcription factor. The arrival of CRISPR–Cas9 gene-editing system in 2012 provided a path forward for haemoglobinopathies. The development of the programme was “remarkably fast”, said Orkin. “It is a perfect example of how the ecosystem can work.”

Vertex and CRISPR have priced the one-off treatment at $2.2 million. It also requires a harsh preconditioning chemotherapy regimen, to make room for the edited cells. The therapy will consequently remain out of reach for many patients. “This is not the end game,” says Orkin, who has his eye on next-generation gene editors and small molecules that might be more accessible.

PS. Un breu missatge per aquells que mitjançant la seva recerca "obren la porta" a tractaments i ho expliquen al Telenotícies. No n'hi ha cap d'aquesta llista del 2024 ni del 2023 d'aquí sota que sigui un d'ells, la porta segueix oberta, o potser no hi havia porta per obrir. Millor no haver d'estar sentint això sempre, sense explicar-ne el resultat.

PS. La història de exa-cel.

PS. The economist sobre el tema

PS. El llistat de medicaments:

Table 1 | CDER approvals in 2023

Drug (brand name)	Sponsor	Properties	Indication
Lecanemab (Leqembi)a	Eisai/Biogen	Amyloid-β-targeted mAb	Alzheimer disease
Bexagliflozin (Brenzavvy)	Theracosbio	SGLT2 inhibitor	Glycaemic control in type 2 diabetes mellitus
Pirtobrutinib (Jaypirca)	Loxo/Eli Lilly	BTK inhibitor	Mantle cell lymphoma
Elacestrant (Orserdu)	Stemline	ER antagonist	ER-positive, HER2-negative, ESR1-mutant breast cancer
Daprodustat (Jesduvroq)	GSK	HIF-PH inhibitor	Anaemia caused by CKD for adults on dialysis
Velmanase alfa (Lamzede)a	Chiesi	Recombinant α-mannosidase	Non-CNS manifestations of α-mannosidosis
Sparsentan (Filspari)	Travere	Endothelin and angiotensin II receptor antagonist	Proteinuria in primary IgA nephropathy
Omaveloxolone (Skyclarys)	Reata/Biogen	Mechanism unknown, NRF2 activator	Friedrich’s ataxia
Zavegepant (Zavzpret)	Pfizer	CGRP receptor antagonist	Migraine
Trofinetide (Daybue)	Acadia	Mechanism unknown	Rett syndrome
Retifanlimab (Zynyz)a	Incyte	PD1-targeted mAb	Merkel cell carcinoma
Rezafungin (Rezzayo)	Cidara	Echinocandin antifungal	Candidemia and invasive candidiasis
Leniolisib (Joenja)	Pharming	PI3Kδ inhibitor	Activated PI3Kδ syndrome
Tofersen (Qalsody)	Biogen	SOD1-targeted ASO	SOD1 amyotrophic lateral sclerosis
Pegunigalsidase alfa (Elfabrio)a	Chiesi	PEGylated recombinant α-galactosidase Α	Fabry disease
Fezolinetant (Veozah)	Astellas	Neurokinin 3 receptor antagonist	Hot flashes caused by menopause
Perfluorohexyloctane (Miebo)	Bausch + Lomb	Semifluorinated alkane	Dry eye disease
Epcoritamab (Epkinly)a	Genmab/AbbVie	CD20 × CD3 T-cell engager	DLBCL and high-grade B-cell lymphoma
Sulbactam, durlobactam (Xacduro)	Entasis	β-lactam antibacterial plus a β-lactamase inhibitor	Hospital-acquired and ventilator-associated bacterial pneumonia caused by susceptible ABC
Nirmatrelvir, ritonavir (Paxlovid)	Pfizer	SARS-CoV-2 main protease inhibitor plus a CYP3A inhibitor	Mild-to-moderate COVID-19
Flotufolastat F18 (Posluma)	Blue Earth	Radioactive diagnostic agent	PET imaging in prostate cancer
Sotagliflozin (Inpefa)	Lexicon	SGLT1/2 inhibitor	Heart failure
Glofitamab (Columvi)a	Genentech	CD20 × CD3 T-cell engager	DLBLC or large B-cell lymphoma
Ritlecitinib (Litfulo)	Pfizer	JAK3 inhibitor	Alopecia areata
Rozanolixizumab (Rystiggo)a	UCB	FcRn-targeted mAb	AChR- or MuSK-antibody-positive gMG
Somatrogon (Ngenla)a	Pfizer	Human growth hormone analogue	Growth hormone deficiency
Nirsevimab (Beyfortus)a	AstraZeneca	RSV F protein-targeted mAb	RSV lower respiratory tract disease
Quizartinib (Vanflyta)	Daiichi Sankyo	FLT3 kinase inhibitor	AML
Lotilaner (Xdemvy)	Tarsus	Ectoparasiticide	Demodex blepharitis
Zuranolone (Zurzuvae)	Sage	GABAA receptor PAM	Postpartum depression
Avacincaptad pegol (Izervay)	Iveric/Astellas	C5-targeted aptamer	Geographic atrophy secondary to AMD
Talquetamab (Talvey)a	Janssen	GPRC5D × CD3 T-cell engager	Multiple myeloma
Elranatamab (Elrexfio)a	Pfizer	BCMA × CD3 T-cell engager	Multiple myeloma
Palovarotene (Sohonos)	Ipsen	Retinoic acid receptor agonist	Fibrodysplasia ossificans progressiva
Pozelimab (Veopoz)a	Regeneron	C5-targeted mAb	CHAPLE disease
Motixafortide (Aphexda)	Biolinerx	CXCR4 inhibitor	Hematopoietic stem cell mobilization for autologous transplantation in multiple myeloma
Momelotinib (Ojjaara)	GSK	JAK1/2, ALK2 inhibitor	Myelofibrosis in adults with anaemia
Gepirone (Exxua)	Fabre-Kramer	5HT1A receptor agonist	Major depressive disorder
Cipaglucosidase alfa (Pombiliti)a	Amicus	Recombinant α-glucosidase	Pompe disease
Nedosiran (Rivfloza)	Novo Nordisk	LDHA-targeted siRNA	Primary hyperoxaluria type 1
Etrasimod (Velsipity)	Pfizer	S1P receptor modulator	Ulcerative colitis
Zilucoplan (Zilbrysq)	UCB	Complement C5 inhibitor	AChR-antibody positive gMG
Bimekizumab (Bimzelx)a	UCB	IL-17A/F-targeted mAb	Plaque psoriasis
Vamorolone (Agamree)	Santhera	Corticosteroid	Duchenne muscular dystrophy
Mirikizumab (Omvoh)a	Eli Lilly	IL-23-targeted mAb	Ulcerative colitis
Toripalimab (Loqtorzi)a	Coherus	PD1-targeted mAb	Nasopharyngeal carcinoma
Fruquintinib (Fruzaqla)	Takeda	VEGFR1/2/3 kinase inhibitor	Colorectal cancer
Taurolidine, heparin (Defencath)	Cormedix	Thiadiazinane antimicrobial plus an anticoagulant	Incidence of catheter-related bloodstream infections
Repotrectinib (Augtyro)	Bristol Myers Squibb	ROS1 and TRK kinase inhibitor	ROS1-positive NSCLC
Efbemalenograstim alfa (Ryzneuta)a	Evive	Recombinant leukocyte growth factor	Neutropenia
Capivasertib (Truqap)	AstraZeneca	AKT kinase inhibitor	Breast cancer
Nirogacestat (Ogsiveo)	Springworks	γ-secretase inhibitor	Desmoid tumours
Iptacopan (Fabhalta)	Novartis	Complement factor B inhibitor	Paroxysmal nocturnal haemoglobinuria
Birch triterpenes (Filsuvez)	Chiesi	Mechanism unknown	Epidermolysis bullosa
Eplontersen (Wainua)	Ionis/AstraZeneca	TTR-targeted ASO	hATTR with polyneuropathy

aBiologic approval. A, accelerated; ABC, Acinetobacter baumannii-calcoaceticus complex; AChR, anti-acetylcholine receptor; AMD, age-related macular degeneration; AML, acute myelogenous leukaemia; ASO, antisense oligonucleotide; B, breakthrough; CGRP, calcitonin gene-related peptide; CKD, chronic kidney disease; CNS, central nervous system; DLBCL, diffuse large B-cell lymphoma; ESR1, estrogen receptor 1; ER, estrogen receptor; FcRn, neonatal Fc receptor; gMG, generalized myasthenia gravis; hATTR, hereditary TTR amyloidosis; HER2, human epidermal growth factor receptor 2; HIF-PH, hypoxia-inducible factor prolyl hydroxylase; IgA, immunoglobulin A; mAb, monoclonal antibody; MuSK, muscle-specific tyrosine kinase; NSCLC, non-small-cell lung cancer; O, orphan; P, priority; PAM, positive allosteric modulator; PD1, programmed death receptor 1; RSV; respiratory syncytial virus; S, standard; S1P, sphingosine 1-phosphate; siRNA, small interfering RNA; TTR, transthyretin. Source: Drugs@FDA.

Table 2 | Selected CBER approvals in 2023

Biologic name (brand)	Sponsor	Properties	Indication
Fc-vwf-xten fusion protein (Altuviiio)	Bioverativ	Recombinant antihaemophilic factor	Haemophilia A
Omidubicel (Omisirge)	Gamida Cell	Nicotinamide modified allogeneic haematopoietic progenitor cell therapy	Neutrophil recovery in patients with haematologic malignancies
Fecal microbiota spores, live (Vowst)	Seres	Bacterial spore suspension in capsules for oral administration	C. difficile recurrence
RSV vaccine, adjuvanted (Arexvy)	GSK	Stabilized prefusion F subunit vaccine	RSV prevention, in over 60s
Beremagene geperpavec (Vyjuvek)	Krystal	HSV-based gene therapy with COL7A1 transgene	Skin wounds in COL7A1-mutated DEB
RSV vaccine (Abrysvo)	Pfizer	Bivalent stabilized prefusion F subunit vaccine	RSV prevention, in over 60s and pregnant women
Delandistrogene moxeparvovec (Elevidys)	Sarepta	AAV-based gene therapy with a micro-dystrophin transgene	DMD patients aged 4–5
Donislecel (Lantidra)	Celltrans	Allogeneic pancreatic islets	Type 1 diabetes patients unable to approach target HbA1c
Valoctocogene roxaparvovec (Roctavian)	Biomarin	AAV-based gene therapy with modified factor VIII transgene	Haemophilia A
Anthrax vaccine adsorbed, adjuvanted (Cyfendus)	Emergent	Protective antigen protein-based vaccine	Post-exposure prophylaxis
Prothrombin complex concentrate, human (Balfaxar)	Octapharma	Prothrombin complex concentrate containing factor II, VII, IX and X, and proteins C and S	Urgent warfarin reversal
Meningococcal groups A, B, C, W, and Y vaccine (Penbraya)	Pfizer	Conjugate and recombinant protein vaccine, pentivalent	Meningococcal disease prevention
Chikungunya vaccine, live (Ixchiq)	Valneva	Live, attenuated chikungunya virus vaccine	Chikungunya virus prevention
ADAMTS13, recombinant (Adzynma)	Takeda	Recombinant rADAMTS13	cTTP
Exagamglogene autotemcel (Casgevy)	Vertex/CRISPR	CRISPR–Cas9-based BCL11a-gene-editing therapy	Sickle cell disease
Lovotibeglogene autotemcel (Lyfgenia)	Bluebird	Lentivirus-based gene therapy with HbAT87Q transgene	Sickle cell disease

AAV, adeno-associated virus; C. difficile, Clostridioides difficile; cTTP, congenital thrombotic thrombocytopenic purpura; DEB, dystrophic epidermolysis bullosa; DMD, Duchenne muscular dystrophy; HbA1c; glycated haemoglobin; HSV, herpes simplex virus; RSV, respiratory syncytial virus. Source: FDA.

 PS. I els medicaments que no s'han aprovat:

Table 3 | Selected rejected drugs of 2023

Drug	Sponsor	Properties	Indication
Donanemab	Eli Lilly	Amyloid-β-targeted mAb	Alzheimer disease
Omecamtiv mecarbil	Cytokinetics	Myosin activator	Chronic heart failure
Inbakicept	ImmunityBio	IL-15 agonist fusion protein	Bladder cancer
Concizumab	Novo Nordisk	TFPI-targeted mAb	Haemophilia A and B
Obeticholic acid (Ocaliva)a	Alfasigma	Farnesoid X receptor agonist	NASH
Zuranolone (Zurzuvae)b	Sage	GABAA receptor PAM	MDD
Avasopasem manganese	Galera	Superoxide dismutase mimetic	Mucositis
Lebrikizumab	Eli Lilly	IL-13-targeted mAb	Atopic dermatitis
Gefapixant	Merck & Co.	P2X3 receptor antagonist	Chronic cough