El negoci de les ciències de la salut

 From Breakthrough to Blockbuster. The Business of Biotechnology

En Gary Pisano va escriure el 2006 un llibre que es va convertir en referència obligada: Science business . The promise, the reality, and the future of biotech. Allà hi havia les claus per entendre l'estat de situació de com funcionava el mercat farmacèutic del moment. I deia:

“It was supposed to be the entrepreneurial biotechnology firms unshackled from tradition and bureaucracy, that would go where big pharmaceutical companies dared not.”

Esperava que les biotecnològiques capgiressin el funcionament de la R+D però malauradament arribava aquesta conclusió:

 “the economics have not worked out and biotechnology firms have moved from the frontier to less risky venues.

Per tant dipositava poques esperances a la biotec i encoratjava a la big pharma a continuar amb els seus esforços interns d'innovació. En realitat, els llibres de negocis hauries d'estalviar-se fer pronòstics perquè el més probable és que s'equivoquin. I així ha estat. Les empreses de biotecnologia són unes 5000 al món, i la majoria 86% no cotitzen a borsa, i estant fent el 70% dels productes en desenvolupament. Entre 1998 i 2016 hi va haver 237 fàrmacs en revisió prioritària fets per 137 empreses, 98 eren biotec i 48 farmacèutiques. La predicció de Pisano s'ha esvaït. Tot això queda explicat en un llibre nou amb dades actuals i que val molt la pena.

Els autors de  From Breakthrough to Blockbuster. The Business of Biotechnology mostren què és la biotecnologia, quines són les empreses i les aliances, com funciona el negoci, què són i fan els seus directius, i quin futur li espera. La biotecnologia es va construir sobretot fonamentada amb dues aportacions: els anticossos monoclonals i l'ADN recombinant. Dues troballes fetes fa 50 anys. Dels anticossos monoclonals en vaig parlar fa uns anys. Ara els grans temes del moment són CRISPR i la biologia sintètica. Però sorprenentment els autors se n'obliden d'aquestes dues aportacions i fan una reflexió sobre la necessària inversió pública en recerca i què s'espera que el sector privat complementi. En definitiva, el futur no està escrit i millor no fer prediccions. Tinc la impressió que separar en dos blocs: biotec i big pharma la innovació en ciències de la vida, ja no té massa sentit i les fronteres s'han difuminat a hores d'ara. El que passa és que cal explicar-ho i trobar un nou marc mental esdevé difícil per ara.

El llibre hauria de ser referència obligada als estudis de ciències de la vida i molt recomanable . 

PS. Fins i tot hi ha una guia docent disponible. 

PS. A The Economist, dades recents.

Com el sector públic i filantròpic va arriscar a la recerca de l'edició genètica

Funding CRISPR: Understanding the role of government and philanthropic institutions in supporting academic research within the CRISPR innovation system 

Sabem que la innovació farmacèutica de l'any 2023 ha estat la primera teràpia aprovada d'edició genètica mitjançant CRISPR. Ara Vertex haurà de pagar una llicència de 100 milions pel cap baix a Broad Institute (Harvard) i al competidor Editas Medicine, per poder comercialitzar-la. 

És un bon moment per preguntar-nos quina ha estat la contribució de finançament públic a la recerca, i per tant si cal considerar fins a quin punt el que s'ha patentat privadament s'ha assolit mitjançant recursos públics.

Això a hores d'ara és complicat de conèixer amb estimacions precises. Però mitjançant la revisió de tots els articles publicats i mirant els reconeixements i agraïments han construït aquest graf que explica prou bé d'on han vingut els recursos per a la recerca, i es veu que fonamentalment venen del govern (punts blaus) i de la filantropia (punts vermells). Aquest és la conclusió del graf referit a Harvard:

The bimodal network model of the Broad/Harvard/MIT system was formed by 28 organizations (12 governmental agencies and 16 philanthropic/charitable organizations) and 111 highly cited papers (14 papers on CRISPR as a biological phenomenon and 97 papers on the development of CRISPR/Cas technologies

 Si cliqueu sobre el gràfic en podreu veure millor el contingut: 

Nota: model de xarxa de cofinançament de la recerca CRISPR/Cas més citada al sistema Broad/Harvard/MIT. Aquesta és una xarxa bimodal de papers i fonts de finançament. La mida dels nodes que representen els articles és una funció del nombre de cites rebudes.

Les vores indiquen quines organitzacions van finançar quins papers. Només els nodes que representen els articles més citats del model de xarxa (més de 500 cites) s'etiqueten amb el seu títol i l'any de publicació i les vores amb llum vermella els relacionen amb la seva organització de finançament.

Els nodes blaus representen agències governamentals, mentre que els nodes vermells representen organitzacions filantròpiques/benèfiques. És important especificar que l'agregació de fonts de finançament està limitada per la informació que els autors proporcionen a la secció d'agraïment dels articles. 

The three clusters are supported by the NIH, which occupies a central position

in the network model, but are cofunded by different sets or organizations. The cluster located in the lower right corner of the network model is formed by papers cofunded by the NIH and the Department of Energy (DoE); a second cluster (upper right corner) is cofunded by a set of philanthropic and governmental organizations; and the third cluster (upper left corner) is cofunded by the Howard Hughes Medical Institute (HHMI) together with a set of U.S. military organizations or programs (Figure 3). There is also an important set of papers exclusively funded by the NIH.

L'altre focus seria el referit a Berkeley, 

the bimodal network model of the UC system was formed by 15 funding organizations (10 governmental agencies and five philanthropic/charitable organizations) and 117 highly cited papers (59 papers on CRISPR as a biological phenomenon and 58 papers on the development of CRISPR/Cas technologies

In the case of the University of California (UC), the cofunding network model (Figure 4) suggests that the top-cited investigations on CRISPR as a biological phenomenon, which is related to the discovery stage of investigation in which the basis of future technologies are built, were mostly supported by the U.S. Department of Energy and the National Science Foundation. A relatively smaller and less cited set of papers was cosupported by the Burroughs Wellcome Fund together with the National Institutes of Health (NIH; Figure 4). On the other hand, the investigations related to the development of CRISPR/Cas technologies at the UC were mostly supported by the NIH together with the National Science Foundation and the HHMI in two respective clusters of papers (Figure 4). There is also an important set of technological development papers funded by the NIH without the participation of other frequent governmental or philanthropic/charitable funding sources

Doncs aquest és el panorama. Resum, no hi hauria CRISPR si no hi hagués hagut inversió pública i filantròpica a la recerca. Desconeixem la magnitud, però sabem les institucions que hi han participat. Malgrat això, s'ha patentat i per tant a hores d'ara és un bé privat finançat públicament o filantròpicament en bona part. I sobretot això ha passat a l'estadi de la recerca on hi ha més risc, he socialitzat el risc i el resultat ha estat apropiat privadament, una altra volta.

PS. M'ha sorprès el paper dels militars en la tecnologia CRISPR i també del Departament d'Energia.

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