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When the first chimeric antigen receptor T-cell (CAR-T) therapy was approved in 2017, there was a general expectation that T-cell receptor T-cell (TCR-T) therapies would follow shortly afterwards and would greatly expand the range of addressable antigens. Despite considerable efforts, CAR-T therapies are still limited to haematological cancers expressing extracellular antigens, such as CD19 or B-cell maturation antigen (BCMA).
Autologous TCR-T therapies can be engineered to target intracellular as well as extracellular peptide antigens presented on the cell surface by human leukocyte antigens (HLAs) and can be more readily used in solid tumors as well as in haematological cancers.
Progress has been slow, however, given the complexities involved in both product design and process development. A decade ago, the field grappled with the issue of toxic and sometimes fatal cross-reactions between epitopes present in proteins expressed in healthy tissue and those contained in the targeted tumor antigens. More recently, the great challenge has been to ensure that engineered TCR-T cells are healthy enough to expand and persist once transferred back into patients.
This year marks an important milestone for the field, as the FDA is due to grant – or deny – approval of Adaptimmune’s T-cell receptor (TCR) T-cell (TCR-T) therapy Afamitresgene autoleucel (afami-cel) for treating melanoma by 4 August 4.
In this episode, we trace the development of the TCR-T technology and sketch out its future possibilities with Selwyn Ho, CEO of TCR-T therapy developer Medigene.
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In 1934, Mary Walker, a pioneering Scottish physician, successfully, albeit transiently, treated a myasthenia gravis patient with physostigmine, a traditional remedy for treating poisoning with curare. She had noticed that the signs and symptoms of myasthenia gravis resembled those caused by curare, a preparation of plant alkaloids used to arm poison arrows by some indigenous peoples in Central and South America. Her clinical observations were extraordinarily accurate. At a molecular level, curare, which induces muscle paralysis, acts as a competitive inhibitor of the neurotransmitter acetylcholine by binding the nicotinic acetylcholine receptor and preventing the transmission of an action potential across the neuromuscular synapse, which would ordinarily lead to muscle contraction.
In myasthenia gravis a similar problem arises due to the presence of autoantibodies that bind to and block the nicotinic acetylcholine receptors expressed on muscle cells. (In a minority of patients, the auto-antibodies may bind to other proteins present in the neuromuscular junction, such as muscle-specific kinase or LPR4). The condition, which literally means ‘serious muscle weakness’, is highly variable. The muscles affected include those involved in controlling the movement of the eyes and eyelids, facial expression, chewing, speaking, and swallowing. Additional damage to the neuromuscular synapse develops through the activation of the complement system. Although most people who have the condition have a normal life expectancy, a minority experiences life-threatening crises, when the muscles that control breathing cannot function. They require ventilator assistance and therapeutic interventions, such as plasma exchange or intravenous immunoglobulin.
Walker’s remedy, physostigmine, a natural product isolated from a number of tropical plant species, was an early example of a cholinesterase inhibitor, which boosts levels of endogenous acetylcholine by slowing its breakdown. Cholinesterase inhibitors remain a mainstay of therapy along with immunosuppressive therapies and surgical removal of the thymus, which remains active in some patients, and which may contribute to their immune dysfunction. In more recent years, antibody-based therapies that target either complement activation or the neonatal Fc receptor (which maintains IgG antibodies, including autoantibodies, in circulation) have come to the fore. CAR-T cell therapies are also in the mix, although the data here are so far mixed. But the long tradition of innovation in treating myasthenia gravis continues.
Companies mentioned in this episode:
Ablynx, Alexion, Argenx, AstraZeneca, Cartesian Therapeutics, Harbor Biomed, Johnson & Johnson, Kyverna Therapeutics, NMD Pharma A/S, UCBSend us a text
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Puuttuva jakso?
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Melanoma has been at the very centre of the cancer immunotherapy revolution over the past decade and a half. The CTLA-4 inhibitor Yervoy (ipilimumab), which gained approval in 2011, was the first agent to demonstrate a survival improvement in a phase 3 trial for metastatic melanoma. It was also the first immune checkpoint inhibitor to gain approval, and it kick-started a whole new era in cancer therapy, based on jamming the cancer’s immunosuppressive signals to enable patients’ T-cells to attack cancer cells.
The first PD-1 inhibitors followed shortly afterwards, and these proved even more active. Combinations proved even more potent again: patients on Yervoy and Opdivo (nivolumab, a PD-1 inhibitor) had median overall survival of 72 months on the CheckMate-067 trial which Bristol Myers Squibb conducted – 49% of patients treated were still alive after six and a half years, and 77% of them were no longer on treatment. The same company recently gained approval for another combination, Opdualag (relatlimab, a LAG-3 inhibitor, and the PD-1 inhibitor nivolumab), which offers similar levels of efficacy but causes less side effects. In parallel, small molecule kinase inhibitors have also proven active, in melanomas with mutations in the BRAF proto-oncogene, which leads to a cellular growth switch being turned permanently on.
Despite these advances, many patients eventually relapse, and work is ongoing to address the problem. The first tumor infiltrating lymphocyte therapy gained approval earlier this year, and others are in development. The first individualised cancer vaccine is also nearing approval. The hope is that these new therapies will help at least some relapsed patients to achieve further long-lasting remissions.Companies & organisations mentioned in this episode:
Amgen, Biontech, Array Biopharma, Bristol Myers Squibb, Daiichi Sankyo, Evaxion Biotech, Iovance Biotherapeutics, Merck, Moderna Therapeutics, National Cancer Institute, Obsidian Therapeutics, Pfizer, Plexxikon & Regeneron Pharmaceuticals.Send us a text
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This is a sobering episode that traces the history of the treatment of brain cancer – principally malignant glioma, since it is the most common diagnosis in a thankfully rare oncology indication – and how, unlike many of the indications we have discussed, the treatment options have been limited. The diagnosis of brain cancer often takes too long, partly because headaches and behavioural changes divert patient referrals to other specialities before patients end up at the door of a neurosurgeon after a CT scan. Surgical removal of tumours, chemotherapy and radiation then remained the staple of care for decades. Even the Gliadel wafer was a combination of these older interventions.
And while surgical debulking, chemo- and radiotherapy will remain in the treatment armoury for brain cancers, more recently there have been developments from biotech and pharma companies that are changing the treatment landscape. The recent approval of the BRAF, MEK and RAF kinase inhibitors that combine specific tumour-associated metabolic inhibition and the molecular genetic profile of tumours have brought modern drug discovery and development to the treatment of brain cancer. But there remain significant challenges in the form of access of new agents to tumours in the brain because of the blood-brain barrier. Even here, medicinal chemists are turning their attention to optimizing the brain penetrant potential of new molecules.
To bring us up to date, and offering much future hope, there are the clinical trials of classes of agents that have proven their worth in other oncology indications like PARP inhibitors, the PD-1 inhibitors, immune-oncology in general, and even CAR-T cellular therapies, that will hopefully add to the diversity of therapeutic options to treat brain cancer. While individual case reports are interesting, we also discuss one remarkable recently publicized combination of many current and experimental therapies that has galvanized hope for these patients.
This episode is dedicated to the patients who have sadly succumbed to brain cancer, including Jacob Whitehead and Nick Bowen and their families. Our commiserations and hopes for the future.Companies mentioned in this episode:
Eisai, Inc., Novartis, AG, Day One Biopharmaceuticals, Servier, Medicenna Therapeutics, AnHeart Therapeutics, NeoImmuneTech, Nerviano Medical Sciences, Merck KGaA, Aveta Biomics, Moderna, Inc. Merck & Co., Inc.Send us a text
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Ophthalmology has long been a fruitful area for biotechnology innovation. In highly prevalent conditions associated with ageing, such as age-related macular degeneration, or with chronic disease, such as diabetic macular oedema, vascular endothelial growth factor inhibitors have made important contributions to stabilizing vision over the past two decades. Incremental innovation has steadily improved efficacy while lowering the frequency of injections. And newer targets, such as components of the complement cascade and angiopoietin, are extending the range of therapeutic options available.Progress in inherited retinal disease (IRD) has been slower, however. No gene therapy has gained approval in an IRD since Luxturna (voretigene neparvovec) did so in 2017. Moreover, Luxturna, which is approved for treating biallelic RPE65 mutation-associated retinal dystrophy, has not been a commercial success, while some of the bigger players have written off billions of dollars in R&D investments because of acquisitions that have failed to deliver.
Classical gene replacement approaches continue to be challenging because of the huge variety of genes associated with IRD – about 270 have been described. Developing individual gene therapies for each is not feasible with current technologies. A newer wave of ‘mutation-agnostic’ gene therapies has moved into the clinic in the last year. These do not address a specific disease-causing mutation but aim to slow the rate of vision loss by improving the metabolic status of damaged photoreceptor cells. Exon editing and cellular reprogramming are at an earlier stage of development, but could also provide ways of addressing multiple disease-associated mutations with a single therapy. The field has never been short of creative ideas – but it needs some clinical success.
Companies mentioned in this episode:
Ascidian Therapeutics, Beacon Therapeutics, Biogen, Editas Medicine, Endogena Therapeutics, Genentech, Gyroscope Therapeutics, Johnson & Johnson, MeiraGTx, Nightstar Therapeutics, Novartis, Ocugen, Ophthotech, Pfizer, Rezolute, Roche, SparingVision, Spark Therapeutics, Thrombogenics, ViGeneronSend us a text
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For all the extraordinary progress we have seen in basic biological research and in the development of advanced therapies, allergy is an area that seems to be stuck and badly in need of innovation. For some, an allergy may be little worse than an irritant, but for those with severe allergies to certain foods or insect stings, it may be a matter of life and death.
The immunotherapy approaches that are still the basis of many development efforts were originally pioneered by Leonard Noon and John Freeman over a century ago. The basic concept is unchanged – the idea is to first diagnose and then desensitize the patient by exposing them to gradually increasing amounts of allergen.
An informal cottage industry of office-based allergists has developed in Europe and the US based around this idea. Companies like DBV Technologies and Aimmune Therapeutics have attempted to put the field on a more solid evidential footing by conducting randomised controlled trials, but clinical and commercial success have both been difficult to obtain.
Antibody developers long used to developing therapies for conditions such as allergic asthma and atopic dermatitis have entered the fray in more recent times. More than two decades on from its original approval, Xolair (omalizumab), an antibody that binds IgE antibodies, gained approval this year for managing multiple food allergies, and Regeneron Pharmaceuticals is in phase 3 with an antibody cocktail for managing birch allergen. But for those with severe allergies, avoidance remains the best protection. Antibody therapies can lower the risk of anaphylaxis in the event of an accidental exposure – but they can’t eliminate it.
Companies mentioned in this episode:
Aimmune Therapeutics, DBV Technologies, Genentech, Nestlé, Regeneron Pharmaceuticals, Stallergenes GreerSend us a text
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A couple of years ago, PROTACs were ubiquitous. Start-ups were devising increasingly clever ways of making them, while large pharma companies were queuing up to tap into their expertise and their development programs. Proteolysis-targeting chimeras, to give them their full title, emerged as a clever and versatile way of degrading, with exquisite selectivity, disease-associated proteins that were hard to drug by conventional means.
First described over two decades ago, by Kathleen Sakamoto, Raymond Deshaies, and Craig Crews, they comprise ‘heterobifunctional’ small molecule drugs that bind a protein of interest at one end and an E3 ubiquitin ligase at the other. This triggers the sequential addition of several ubiquitin molecules, which ‘tag’ the protein for degradation in the proteasome, a key element in the cell’s waste management machinery. Over a decade later, scientists at Celgene (now Bristol Myers Squibb) discovered that their blockbuster immunomodulatory multiple myeloma drug Revlimid (lenalidomide) was in fact a prototypical PROTAC, and this set the stage for a massive influx of investment and development across the biotech industry.
PROTACs target intracellular proteins only, but several other analogous approaches have emerged in order to address extracellular proteins, membrane proteins or non-protein metabolites. These employ alternative targeting strategies either to direct a molecule of interest into other degradation pathways, involving lysosomal degradation or autophagy, for example, or to prevent it from fulfilling a function needed for the cell’s survival.
The field appears to have grown quiet of late – but it has by no means run out of steam. The early leaders – chief among them Arvinas – are now in the clinic and evaluating whether their innovative science will translate into clinical benefit for patients. Most of the initial development effort is focused on cancer and, to a lesser extent, on autoimmune disease. But if PROTACs – and their relations – can be shown to work, the clinical possibilities are very wide indeed.Companies mentioned in this episode:
Arvinas, Avilar Therapeutics, Bayer, Biogen, Bristol Myers Squibb, C4 Therapeutics, Celgene, Cullgen, Genentech, Halda Therapeutics, Nurix Therapeutics, Frontier Medicines, Kymera Therapeutics, Millennium Pharmaceuticals, Lycia Therapeutics, Monte Rosa Therapeutics, Novartis, Nurix Therapeutics, Paq Therapeutics, Pfizer, Roche, Sanofi, Vertex Pharmaceuticals, Vividion TherapeuticsSend us a text
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Over 10% of the world’s population – or 850 million people – are estimated to have kidney disease, and the problem is growing rapidly. The vast majority lives in low-income or low-and-middle-income countries, and, without access to primary healthcare, may be unaware of the problem until it is too late – organ failure and early death follow. Only dialysis and organ transplant can prolong the life of patients with kidney failure, but neither is hugely scalable, particularly in low-resource settings.
Although asymptomatic until its later stages, kidney disease is easily diagnosed through urine and blood tests. In low-income countries, malnutrition, dehydration, infection and exposure to environmental toxins are important risk factors for kidney disease. In wealthy countries, kidney disease is often seen as a complication of other conditions, such as diabetes or high blood pressure. The treatments administered to patients reflect these lead-in indications – lowering blood sugar levels, lowering blood pressure and blockade of the renin-angiotensin-aldosterone system (which controls blood pressure and fluid balance) are all important interventions. The advent of newer classes, such as sodium/glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide 1(GLP-1) receptor agonists, and endothelin receptor antagonists have further improved the prospects of those patients who have access to them.
The cause of many cases of kidney failure remains unclear, however, although lowering inflammation and fibrosis are two additional approaches that have promise. Historically, kidney disease has not been a major focus of innovative biotechnology companies, although several large transactions in recent times indicate that that may be changing. Vertex Pharmaceuticals recently entered a $4.9 billion acquisition agreement with Alpine Immune Sciences, and Novartis acquired Chinook Therapeutics last year for $3.2 billion upfront. The focus of both deals is IgA nephropathy (or Berger’s disease), which arises from the damaging deposition of antibody complexes in the kidney.
Definitive data from large-scale phase 3 trials is still several years away. In the meantime, a recent consensus statement (Francis, A., et al., 3 Apr. 2024, Nat. Revs. Nephrol.) from several expert groups has called for the inclusion of kidney disease on the World Health Organization’s list of priority non-communicable diseases and the recognition of its varied causes and drivers in different regions and populations.Companies mentioned in this episode:
Alpine Immune Sciences, Atara Biotherapeutics, Bayer, Boehringer Ingelheim, Chinook Therapeutics, CSL Vifor, GSK, Novartis, Sanifit, Travere Therapeutics, Renalys Pharma, Vertex PharmaceuticalsSend us a text
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Human longevity is a precious thing. Some people receive a tragically short amount of it. Others who have it in abundance want even more of it – and a reasonable chunk of the biopharmaceutical industry has organised itself around the goal of delivering it to them.
Age-associated diseases encompass a very broad area of human disease, including cancer, cardiovascular disease, and neurodegenerative disease, among many others. These have, obviously, been mainstream concerns for drug developers for decades, but in more recent years, new biological insights into the molecular and cellular dimensions of senescence have opened up new possibilities for biotech firms focused on interrogating the ageing process.
Some of the early efforts flamed out, however. GSK’s $720 million acquisition of Sitris Pharmaceuticals was a notorious example. And some of other concepts that have emerged from academic research in animal models, such as restricting food intake, blocking telomere shortening and administering senolytic drugs have either proved unsuccessful or unworkable in humans.
It may be that the pharmaceutical industry can only make a modest contribution here – ageing is a biological process rather than a disease, even if some techno-utopian dreamers think that death is merely the outcome of a series of system bugs that can be fixed. They are fixed on attaining longevity escape velocity – a wholly theoretical scenario in which technologically enabled improvements in life expectancy outpace the ageing process. For the rest of us, a healthy old age for all would be a welcome outcome – and we’re a very long way from obtaining that.
Companies mentioned in this episode:
Abbvie, Arivale, Calico Life Sciences, GSK, Sitris PharmaceuticalsSend us a text
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Therapeutic cancer vaccines have had a long and chequered history. The BCG (Bacillus Calmette-Guérin) vaccine, originally developed to protect against tuberculosis in the 1920s, was adopted back in the 1970s as treatment for bladder cancer. When delivered locally to the organ, it elicits an anti-tumor immune response.
Progress in recent decades has been painfully slow, however. Only a clutch of therapeutic cancer vaccines has gained approval, and their performance has been decidedly mixed. Provenge (sipuleucel-T), originally developed by Dendreon Corp., exemplifies the field’s unfulfilled promise. The dendritic cell therapy was approved in prostate cancer fifteen years ago on the basis of a four-month survival benefit in clinical trials. It supposedly ‘trained’ patients’ immune systems to attack their tumors. But its high cost and complicated manufacturing process were its undoing.
More recently, Gritstone Bio spooked investors with lacklustre data from a phase 2 trial in colorectal cancer of its Granite cancer vaccine. Its individualised approach involved presenting to each patient’s immune system up to 20 (tumor-derived) neoantigens, in a prime-boost strategy based on a modified adenovirus vector and a self-amplifying RNA construct. But Candel Therapeutics is currently riding high on the back of promising survival data in pancreatic cancer for CAN-2409. BioNTech has also reported good, albeit early stage, pancreatic cancer data from an mRNA vaccine it is developing with Genentech. Its great mRNA rival Moderna is further advanced with V940 (mRNA-4157), which it is developing with Merck. It has shown promising survival benefits in melanoma, and a late-stage trial in that indication is underway, and the partners have also commenced a phase 3 study in lung cancer.
Companies mentioned in this episode:
Amgen, BioNTech, Candel Therapeutics, Curevac, Dendreon Corp., Genentech, Gritstone Bio, Iovance Biotherapeutics, Merck, Moderna & Northwest Biotherapeutics.Send us a text
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The flow of money is a constant preoccupation of the biotechnology sector, because without it nothing gets done. So, whether the markets are up or down, and whether investors are buying or selling is important, even if it is secondary to the actual business of biotech, which is the discovery and development of therapies that offer improvements over what is currently available.
Investor sentiment in biotech is cyclical, based both on external macroeconomic factors and on the sector’s internal dynamics. A recent flurry of investment activity in the public and private markets has prompted some to suggest that biotech is now in full-blown recovery mode. The IPO window appears open, and several large transactions have occurred. In the public markets, the overall gains are still distinctly modest, however.
The Nasdaq Biotechnology Index is actually down 1% since the start of the year, although it is up 12% over the past year. In venture capital, the picture looks a little more rosy, as several deals north of $100 million have been disclosed in recent weeks, including Mirador Therapeutics’ eye-catching $400 million financing to fund its efforts to discover “precision” drugs for immune-mediated inflammatory and fibrotic diseases, based on new insights into human genetics and disease biology.
As always, the innovative potential of individual companies will influence the size of a given deal. Cyclical considerations aside, that too is what keeps investors coming back to biotech. And there is plenty of room for more innovation in the sector.
Companies mentioned in this episode:
Acusphere, Alto Neuroscience, Ark Therapeutics, AstraZeneca, Biontech, Bristol Myers Squibb, Capstan Therapeutics, CG Oncology, Fog Pharma, Fusion Pharmaceuticals, Karuna Therapeutics, Kyverna Therapeutics, Mirador Therapeutics, Pfizer, Roche, Sionna Therapeutics & Vertex Pharmaceuticals.Send us a text
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The failure of Relyvrio in a post-approval phase 3 study in amyotrophic lateral sclerosis (ALS) means its days as a commercial drug are probably numbered. It initially gained approval in Canada in June 2022 (where it is, confusingly, known as Albrioza) and secured FDA approval the following September.
Both approvals rested on the 24-week phase 2 ‘Centaur’ trial, in which the drug showed modest effects as compared with placebo in slowing patients’ decline in physical functions. Those data were published in the New England Journal of Medicine (Paganoni et al., 3 Sep. 2020). A follow-up analysis, published in the Annals of Clinical and Translational Neurology (Paganoni et al., 9 Oct. 2023) even suggested it could have a survival benefit. But the Phoenix trial recruited almost five times as many patients (664 vs. 137) and was twice as long, which means it is a far more rigorous test of the drug’s effects. The setback has raised questions about the FDA’s apparent leniency in approving a drug that its own expert advisory panel initially rejected.
Its approval followed a second such hearing, which, in the absence of new data, is highly irregular. If nothing else, the episode highlights the difficulty of developing effective therapies for highly varied and complex conditions whose disease biology is still not fully understood. Relyvrio’s mechanism was not a settled matter either. The drug, a fixed-dose combination of sodium phenylbutyrate and taurursodiol, ameliorates endoplasmic reticulum stress and mitochondrial dysfunction, according to its developer.
According to the FDA product label, its mechanism in ALS patients is unknown. There is an urgent need for effective therapies in ALS. Insights from genetic forms of the condition (which account for about 10% of cases) are helping scientists to unpick some of its molecular underpinnings. In time, these may help to form the basis of therapies that could help patients with either form of the condition. But for patients living with the condition at present, therapeutic options are still tragically limited.
Companies mentioned in this episode:
Amylyx Pharmaceuticals, Biogen, Ionis Pharmaceuticals, QurAlis, Sarepta TherapeuticsSend us a text
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A 40% share price drop after an investigational drug hits the primary endpoint of a phase 3 trial is not typical. But that’s what happened to Ironwood Pharmaceuticals when it reported data from a trial of apraglutide in patients with intestinal failure due to short bowel syndrome (SBS-IF).
The condition arises from the loss of gut function following surgical removal of a large portion of the small intestine due to conditions such as severe inflammatory bowel disease or cancer in adults or congenital problems or necrotizing enterocolitis in infants. Because patients are then unable to absorb sufficient nutrients or water, they rely on parenteral nutrition and fluid delivered directly to the bloodstream by a catheter. It’s far from ideal. Complications and infections can occur, and patients’ quality of life is severely affected. The goal of therapy is to reduce the volume of parenteral support needed. A secondary goal is to reduce the number of days per week when it needs to be administered.
Apraglutide mimics the effects of a natural peptide hormone, GLP-2, which is normally released in response to food intake. It aids nutrient absorption by slowing the passage of food through the intestine and promoting the regrowth of intestinal tissue. It is rapidly broken down and cleared from the system, however. Therapeutic analogues have been developed to resist degradation and act over longer timescales.
Ironwood reported that apraglutide reduced patients need for parenteral support by 25.5% from baseline levels – the reduction in those on placebo was 12.5%, so the net treatment effect appears modest but real. Some 43% of patients on apraglutide were able to do without parenteral support for at least one additional day per week, as compared with 27.5% of those in the placebo arm. Ironwood’s problem is that it pitting apraglutide against a long-established competitor, Takeda’s Gattex (teduglutide), another GLP-2 analogue. Generic competition cannot be too far away, as Gattex, a notoriously expensive drug, is about to lose patent protection. Apraglutide has one key advantage – it is dosed on a weekly basis, whereas Gattex requires daily administration. Whether that is enough to make it a successful product is not clear at this point. But some investors clearly think it isn’t.Companies mentioned in this episode:
9Meters Biopharma, Hanmi Pharmaceutical, Ironwood Pharmaceuticals, Merck KGaA, NPS Pharmaceuticals, Serono, Shire, Takeda, VectivBio, Zealand PharmaceuticalsSend us a text
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By late June or early July we’ll know whether Alnylam’s decision to alter the design of its phase 3 ‘Healios B’ study of Amvuttra (vutrisiran) in transthyretin amyloidosis with cardiomyopathy (ATTR-CM) was a good one. The short-interfering RNA (siRNA) drug is already approved in ATTR with polyneuropathy (ATTR-PN), a debilitating, fatal condition in which misfolded transthyretin proteins clump together and create damaging deposits in the peripheral nerves.
But about ten times as many patients develop ATTR-CM, in which protein deposition occurs in cardiac tissue and gives rise to a form of heart failure. Alnylam is, therefore, attempting to establish Amvuttra in this category as well.
An earlier drug from the same stable, Onpattro (patisiran), failed to deliver in ATTR-CM, but the company argues that it needed a longer, larger trial to detect the survival signals it is now seeking with Amvuttra in the Healios B study. Pfizer is the current category leader in this space with its Vyndaqel (tafadamis) product family.
Alnylam maintains that extending the duration of the follow-up on Healios B will improve the study’s statistical power and strengthen its hand when commercializing the product. But as Alnylam’s leadership knows, changing the goalposts mid-trial can be a risky move. It’s a big play from CEO Yvonne Greenstreet and chief medical officer Pushkal Garg.
Companies mentioned in this episode:
Alexion Pharmaceuticals, Alnylam Pharmaceuticals, Athena Neurosciences, AstraZeneca, Eidos Therapeutics, FoldRx, Ionis Pharmaceuticals, Pfizer, Neurimmune, Novo Nordisk, Prothena BiosciencesSend us a text
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Novartis’s recent €2.7 billion ($2.9 billion) offer for Morphosys is the very stuff of biotechnology. The medium-sized deal adds two clinical-stage cancer drug candidates to its pipeline.
Both operate through epigenetic mechanisms – they aim to alter dysfunctional gene expression programs and thereby interfere with the signals that maintain cancer growth. Pelabresib, a potential first-in-class inhibitor of bromodomain and extra-terminal motif (BET) proteins, has completed a phase 3 trial in myelofibrosis, a rare bone marrow cancer which disrupts red blood cell production. Tulmimetostat (formerly CPI-0209), an inhibitor of enhancer of zeste homolog 2 (EZH2), is in phase 1/2 trials in solid and haematological cancers.
Behind the headlines, of course, lies over 30 years of European biotechnology history. Morphosys was the flagship firm in Munich’s biotech cluster and for long a leader in antibody discovery and development. It entered a string of large-scale deals with the likes of Novartis (again), Roche, GSK, Celgene (now Bristol Myers Squibb), and Johnson & Johnson.
Although its HuCal platform did deliver at least one blockbuster, in the form of J&J’s interleukin-23 inhibitor Tremfya (guselkumab), Morphosys failed ultimately to capture sufficient value to secure its future as a standalone antibody developer – unlike its more successful European rivals Genmab and Argenx. CEO Jean-Paul Kress and his team executed a bold pivot in 2021 by buying Constellation Pharmaceuticals for $1.7 billion and jettisoning Morphosys’s antibody heritage. That, essentially, is what Novartis is now buying.Companies mentioned in this episode:
Abbvie, Abbott Laboratories, Abcellera, Ablynx, Argenx, Celgene, Cambridge Antibody Technology, Constellation Pharmaceuticals, Chiron, Dyax, Genmab, GSK, Incyte, Johnson & Johnson, Morphosys, Novartis, Roche, Royalty Pharma, XencorSend us a text
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Hereditary angioedema (HAE), arguably, represents an ideal case of the Orphan Drug rules in action. Because of the incentives on offer, a mini-cluster of firms has, over the past fifteen years, developed a well-stocked cabinet of therapies for this rare disease.
The condition is linked to deficiencies in C1 esterase inhibitor activity and results in dysregulation of the kinin-kallikrein pathway, which is involved in regulating inflammation, blood pressure, and coagulation. The ultimate culprit is bradykinin, a potent, pro-inflammatory vasodilator.
People living with HAE are at risk of regular acute attacks, which are characterised by fluid release from leaky blood vessels, swelling, inflammation, and pain. Various organ and tissue systems can be affected, including the larynx, which can result in asphyxiation.
The HAE space represents the evolution of the wider biotechnology industry in microcosm – plasma-derived C1 esterase inhibitor products were followed by recombinant equivalents (including one obtained from transgenic rabbits, which is itself an important branch of biotech history). Small molecule and antibody drugs were brought to bear on different targets within the kinin-kallikrein signal cascade. These have reduced, but not eliminated episodes. There is room for further innovation – and it is coming.
Intellia Therapeutics recently published compelling, albeit preliminary, data for its CRISPR-Cas9-based gene editing therapy, while siRNA and antisense molecules are also in clinical development. Can these gene-based medicines supplant the incumbents? Time – and more data – will tell.
Companies mentioned in this episode:
ADARx Pharmaceuticals, Astria Therapeutics, BioCryst Pharmaceuticals, CSL Behring, Dicerna Pharmaceuticals, Intellia Therapeutics, Ionis Pharmaceuticals, Jerini, Lev Pharmaceuticals, Pharming, Shire, Regeneron Pharmaceuticals, Takeda, ViropharmaSend us a text
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Non-alcoholic steatohepatitis (NASH) and its precursor non-alcoholic fatty liver disease (NAFLD) have recently been redesignated as MASH and MASLD – metabolic dysfunction-associated steatohepatitis and metabolic dysfunction-associated steatotic liver disease, respectively. What hasn’t changed is the sheer difficulty of establishing clinical efficacy in these indications. They have long been known as a ‘silent killer’, owing to the asymptomatic nature of the pathology. And yet, the gradual accumulation of fat in the liver leads eventually to inflammation (or hepatitis), fibrosis (or scarring), cirrhosis (severe scarring), and, possibly to loss of function, liver failure, and liver cancer. Conducting clinical trials isn’t easy, given the slowly progressing course of the condition. Moreover, they also require numerous invasive tissue biopsies, to assess whether an investigational agent is having an effect.
Madrigal Pharmaceuticals will learn on or before 14 March next whether the FDA will approve its application for resmetirom, which activates the thyroid hormone beta-receptor. If it’s successful, it could be the first of a slew of drugs that address a range of different targets. But will the rise of the skinny jabs (AKA the Glucagon-like receptor 1 agonists) provide an effective way of preventing fatty acid liver disease from progressing in the first place?
Companies mentioned in this episode:
AstraZeneca, Alnylam Pharmaceuticals, Boehringer Ingelheim, Intercept Pharmaceuticals, Ionis Pharmaceuticals, Madrigal Pharmaceuticals, Novo Nordisk, Madrigal Pharmaceuticals, Zealand PharmaSend us a text
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Sanofi’s partial acquisition of Inhibrx recalls earlier transactions, such as Pfizer’s acquisition of BioHaven or, to go back even further, Johnson & Johnson’s acquisition of Actelion, in which assets deemed surplus to the acquirer’s needs were spun out into new entities.
In the case of Inhibrx, Sanofi wanted just one programme, INBRX-101, its investigational drug for alpha1-anti-trypsin deficiency (AATD), a genetic condition arising from a point mutation in the SERPINA1 gene, which encodes alpha-1 antitrypsin. The protein is produced in and exported from the liver and plays a key protective rule in the lungs.
Sanofi is paying $1.7 billion upfront and could pay another $296 million in connection with the programme’s progress. The rest of Inhibrx’s assets, which include several clinical-stage oncology programmes, will be spun out into a new company, Inhibrx Biosciences. This will have start-up capital of $200 million, and Sanofi will hold an 8% stake.
The dynamics that influence these asset-selective deals differ all the time – and reflect the specific strategies and needs of the acquirer and its target. Sanofi has, through its Genzyme acquisition, a large footprint in the rare disease market. Unlike Pompe disease, where its attempted deal with Maze Therapeutics fell foul of the Federal Trade Commission, it is unlikely to run into any problems with its Inhibrx transaction, given the depth of competition in the area. Several plasma-derived replacement products are already on the market, but they are sub-optimal as it is difficult to maintain appropriate levels of AAT. INBRX-101 is also designed to address the lack of functional AAT, but the protein is fused to the Fc portion of an antibody to increase the time it remains in circulation.
A head-to-head phase 2 trial is underway, which will compare the effects of INBRX-101 with those of a plasma-derived product in maintaining functional levels of the protein. AAT protects the lungs from excessive neutrophil elastase activity. The latter enzyme protects against environmental irritants and infectious agents, but it causes severe lung damage if unchecked. People living with AATD can also develop liver disease, as the mutant, misfolded form of AAT cannot be exported from the organ but instead polymerizes and forms pathogenic aggregates that lead to inflammation, fibrosis, cirrhosis and potentially cancer.
Several other approaches to managing the condition are also in development – these include short interfering RNAs and RNA editors, designed to suppress production of mutant AAT, as well as neutrophil elastase inhibitors, designed to minimize damage to the lungs. A number of gene therapy firms aim to promote localized production of AAT in the lungs by producing modified gene therapy vectors for inhalation. But Sanofi is betting that the relative simplicity of the Inhibrx approach will be a winner.Companies mentioned in this episode:
Adverum Technologies, Alveologene, Arrowhead Pharmaceuticals, BioHaven, BioMarin, GSK, Inhibrx, Intellia Therapeutics, Korro Bio, Krystal Biotech, Mereo Biopharma, Pfizer, Sanofi, Takeda, Vertex Pharmaceuticals, Wave Life Sciences
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The use of radiation in medicine began with the work of the great pioneers Marie Curie, her husband Pierre, and Henri Becquerel. In the 1940s, Samuel Hertz, Samuel Seidlin, and William Beierwaltes established radioactive iodine (I-131) as a treatment for overactive thyroid and thyroid cancer.
The effects of radiation are not cell-specific – it is inherently damaging to all cells, so the focus of current development efforts is on delivering a targeted dose of radiation, by attaching a radioisotope to an agent, be it a small molecule, a peptide, or an antibody, that can recognise and bind a protein expressed on the surface of a cancer cell.
Over two decades ago, the approvals of Zevalin (ibritumomab tiuxetan) and Bexxar (tositumomab), CD20-targeting antibodies labelled with Yttrium-90 or Indium-111 and with I-131, respectively, kicked-started the modern era of radiopharmaceutical development. Neither was a commercial success, however, as the naked antibody Rituxan (rituximab), which also targets CD20, dominated the market for CD20-positive lymphomas. Although perhaps not quite as potent as its radioactive rivals, Rituxan was far easier to handle and administer. It was also far easier to make.
Radiopharmaceuticals production is complicated. At a minimum, these constructs involve a radioisotope, a chelator that binds it, and a linker that connects these to the tumor targeting agent. Moreover, because the radioisotopes used in medicine typically have half-lives of seven to ten days, they cannot be stockpiled – manufacturing is unavoidably on a just-in-time basis. This has led to supply chain problems and product shortages, which can have very serious consequences for patients.
Optimising a radiopharmaceutical’s residence time in a patient’s blood is a key parameter. Too long in the circulation can expose off-target tissues to excessive radiation. Rapid elimination via the kidneys is also problematic, as patients’ tumors may not receive sufficient drug to have a significant impact, while the kidneys may be exposed to too much.
Ratio Therapeutics adds in an additional molecule, an albumin binder, to enable it to ‘tune’ the pharmacokinetic (PK) profile of the drug. Novartis has invested heavily in this modality by acquiring Advanced Accelerator Applications and Endocyte, which gave it ownership of the gastroenteropancreatic neuroendocrine tumor drug Lutathera (lutetium 177 dotatate), and the prostate cancer drug Pluvicto (lutetium-177 vipivotide tetraxetan), respectively. More recently, Eli Lilly & Bristol Myers Squibb have entered the fray, by acquiring Point Biopharma and Rayzebio, respectively. The field is definitely hotting up.
Companies mentioned in this episode:Abdera Therapeutics, Advanced Accelerator Applications, Algeta, Bayer, Bicycle Therapeutics, Bristol Myers Squibb, Eli Lilly, Endocyte, Noria Therapeutics, Novartis, Peptidream, Point Biopharma, Ratio Therapeutics, Rayzebio
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The annual JP Morgan Healthcare Conference, held in San Francisco every January, marks the start of the biotech industry’s new year. It’s the time when biotechnology companies of all shapes and sizes set out their stall for the year ahead, hoping to attract the attention – and the dollars – of big pharma.
It’s the ideal time to take the temperature of the industry. And right now, it appears to be emerging from the big chill of 2023. The Nasdaq Biotechnology Index continues the climb it began in Q4 2023, deals continue to get done, and companies continue to raise cash. And new conversations that lead to future deals get started. Much of the swagger that characterised the meeting during the boom years has gone – and that’s no bad thing. But for those who have struggled to stay afloat during the past year, a recovery will be welcome.
Companies mentioned in this episode:Aiolos Bio, Ambryx, Amgen, AstraZeneca, Bristol Myers Squibb, Cellarity, Eli Lilly, GSK, Isomorphic Labs, Johnson & Johnson, Omega Therapeutics, Pfizer, Novartis, Novo Nordisk, Rayzebio, Roche, & Seagen
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