💉 Carisma’s undercover cancer-killers; Moving from pollution to solutions in Africa; XtalPi’s Singapore connection

#479 | Finding CRISPR’s cousins; Bacteria getting on your nerves; Preserving our medical muses

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Nov 24, 2023

Hello, and welcome back to The Kable, your favourite Friday fun-time read.

Antimicrobial resistance is a growing threat all over the world. The Gambia is no exception. After an analysis revealed an increase in multi-drug resistant tuberculosis and resistance to commonly used antibiotics, the country has developed a National Action Plan on Antimicrobial Resistance for 2023-2027, aligning with its National Health Policy, to implement key measures by 2027, addressing both human health and broader environmental issues.

A recent study highlights a significant issue in sub-Saharan Africa: most people with colorectal cancer receive no or inadequate treatment, despite the potential for cure, leading to mortality rates up to 3.5 times higher than in regions with better healthcare. The study underscores the urgent need for improved diagnosis and treatment options in sub-Saharan Africa, suggesting that even basic care improvements could significantly enhance survival rates and reduce suffering.

XtalPi and Singapore's Experimental Drug Development Centre (EDDC) have expanded their collaboration to focus on applying automated synthesis solutions and large language models in pharmaceutical research, building on their existing partnership in AI-driven targeted therapies for lung cancer. This collaboration will explore automated chemical synthesis and AI-driven drug discovery, leveraging XtalPi's robotics and AI capabilities in EDDC's R&D to enhance drug development processes and create advanced computational tools for therapeutic discovery.

Sanjivani Paranteral has signed an agreement with Hindustan Antibiotics for manufacturing Intravenous (IV) formulations and sets, with a confirmed purchase commitment from Hindustan Antibiotics. This partnership will lead to the establishment of a new manufacturing facility at Pimpri works, Pune, with the aim of producing 50 lakh IV fluid bottles and 10 lakh IV sets per month.

Indian philanthropy organisation ACT for Health and Gates Ventures-funded Global Health Labs are collaborating to support development and scaling of digital and medical technology innovations within India's public healthcare system, aiming to improve access to quality and affordable healthcare for underserved populations.

The European Union is providing €10 million to the WHO to combat infectious diseases and strengthen health service delivery in Afghanistan, aiming to improve preparedness and response systems for disease outbreaks and health emergencies.

The European Commission has authorised a Type II variation for Rubraca (Rucaparib), a PARP inhibitor, now approved as a first-line maintenance treatment for advanced ovarian cancer, regardless of BRCA mutation status, after responding to platinum-based chemotherapy. This approval offers a significant treatment option for patients, with 80% experiencing recurrence and requiring subsequent therapies.

In more approval news, the European Commission has also authorised EirGenix's Trastuzumab biosimilar, EG12014, for treating HER2-positive breast and metastatic gastric cancers, with commercialisation planned by Sandoz.

AstraZeneca has licensed global rights to an experimental drug targeting KRAS G12D mutations from Yousen Jianheng Biopharmaceutical in a deal potentially worth nearly $420 million, marking its second recent transaction with a Chinese firm following a previous pact with Eccogene. The agreement includes an upfront payment of $24 million and up to $395 million in milestones, plus sales royalties, as AstraZeneca aims to accelerate development of treatments for tumours with the KRAS G12D mutation. Good timing too with a separate GlobalData forecast predicting the global market for KRAS-targeting drugs to cross $4 billion by 2029.

Bayer has inaugurated a new state-of-the-art manufacturing facility at its global pharmaceutical headquarters in Berlin, Germany, marking a significant step in its global manufacturing strategy for liquid pharmaceutical dosage forms like injections and infusions. This facility, part of a billion-dollar investment program, features innovative technology and automated processes, aimed at enhancing the production and supply of a wide range of parenteral products, and is set to supply markets in the USA, Europe, and China.

Wegovy, Novo Nordisk's billion-dollar blockbuster anti-obesity drug, is making its Asian debutwith its launch in Japan on February 22 next year, despite Japan's relatively low obesity rates compared to the West. Eligibility for the drug in Japan is based on specific body mass index (BMI) criteria.

Is it a new pandemic? Leading scientists have sought caution over these fears following the WHO's request for more information from China regarding a rise in respiratory illnesses and pneumonia clusters in children. The alert, initially raised by the monitoring service ProMED, has drawn parallels to the early notifications of COVID-19, sparking concerns of another emerging pathogen. However, experts suggest it's more likely to be an increase in common respiratory infections like flu or a resurgence of Covid, especially after the lifting of lockdowns. Chinese health authorities have reported to the WHO that the recent increase in respiratory illnesses and pneumonia clusters in children is linked to the lifting of Covid restrictions and the circulation of known pathogens like mycoplasma pneumoniae, influenza, respiratory syncytial virus (RSV), and adenovirus. The WHO, which had requested this data through the International Health Regulations mechanism, stated that no unusual pathogens have been detected and that the rise in illnesses is a seasonal surge, common post-pandemic, advising continued preventive measures against respiratory diseases.

The WHO’s 2023 review ahead of COP-28 emphasises the need for health to be a priority in national climate change strategies, highlighting progress in integrating health into such plans but stressing the urgency for more action and funding. Despite significant strides in acknowledging health in climate strategies, there is a pressing need for increased, equitable funding and accelerated action, particularly in air pollution reduction and health-specific climate initiatives, to protect human health and promote sustainable development.

And finally, as we say goodbye to this week, nearly 2000 pigs in Hong Kong are saying goodbye to the world after swine flu was reported in one of them.

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The Week That Was

The week that was was eventful, to say the least, with the most significant update being the European Patent Office’s ruling that one of Moderna’s Covid patents was invalid.

Monday brought reports of drug prices in Nigeria soaring as much as 1,000% after GSK’s transition to a third-party direct distribution model in the country. Pharma product traders report that there has been a noticeable scarcity of GSK products nationwide.

Dammam Pharma, a subsidiary of Saudi Pharmaceutical Industries and Medical Appliances Corporation (SPIMACO), has inked an agreement with MSD to manufacture type 2 diabetes medications locally. This will be the first factory in the MENA region to produce type 2 diabetes meds.

In a case of Big Pharma and its Big Problems, Bayer’s Monsanto business was found liable for claims of negligence, design defects, and failure to warn plaintiffs of the potential dangers of using its Roundup weedkiller. A jury in the US has ordered Bayer to pay $1.56 billion to four plaintiffs who claim the weedkiller was the reason they developed non-Hodgkin lymphoma.

At least 539 million schoolchildren around the world do not have access to a functioning toilet in their school. Supported by Unilever, Economist Impact launched research to measure the impact of toilet loss i.e. the economic and social cost of neglected toilets in Ecuador, India, Nigeria, and the Philippines. Globally, we need at least 20 million more basic service school toilets to reach 100% coverage by 2030 – that is a 6x acceleration in our progress since 2015.

Tuesday kicked off with an update about the Bill & Melinda Gates Foundation awarding $16 millionto the Malaria Atlas Project (MAP), the home of the world’s largest malaria database. Part of the BMGF grant will contribute to the establishment of a new MAP Node - housed within the Ifakara Health Institute, Dar es Salaam, Tanzania - in East Africa.

As part of the Paris Agreement, global leaders had aimed to keep warming within 1.5°C above pre-industrial times. But guess what? The UNEP’s annual Emissions Gap report claims that even with countries’ current pledges to limit emissions, the world would be on track to warm by nearly 3°C this century.

Treatments and vaccinations for Alzheimer’s disease haven’t seen much success in the past, but the newly launched Leqembi and Donanemab by Eisai-Biogen and Eli Lilly, respectively, have lent much credibility to the amyloid theory, i.e. the approach of treating the disease by taking on amyloid plaques in the brains of people with early-stage Alzheimer’s. Such success has also revived interest in vaccines for the neurodegenerative disease – these might eventually offer cheaper, easy-to-administer options for millions of people. Reuters highlighted progress in this area.

On Wednesday, South Korea’s SK Biosciences entered a development licensing agreement with Hilleman Laboratories Singapore to jointly develop a low-cost second-generation Zaire ebolavirus vaccine.

Neglected tropical disease (NTD) treatments already suffer a dearth of pharmacokinetic data. When it comes to optimising doses for children, there is even less data. After a Paediatric Drug Optimisation (PADO) exercise that the WHO conducted to identify priority meds and formulations for R&D, yesterday, the WHO released the first-ever PADO priority list; the list promotes R&D for five neglected tropical diseases (NTDs) affecting children of three to five years of age.

Yesterday was another iteration of the endless loop that Indian pharma finds itself in. The country's drug regulator mandated a halt in production for 76 out of 237 pharmaceutical companies. This decision followed risk-based inspections that began last December, uncovering subpar manufacturing standards.

And finally, National Institutes of Health-funded research by chemists from the University of California Los Angeles discovered a much cheaper method to produce required drug moleculesthan currently used inputs and techniques. This process could be a real game-changer for industrial amine production for pharma and potentially a standard production technique across a range of industries.

Newsworthy

New undercover agent in cancer town. Immunotherapies have been game-changers when it comes to cancer treatment, especially for blood cancers. But they aren’t the best answer to solid tumours in breast, lung, or pancreatic cancers. This is because solid tumours are harder for the immune system to detect as they are entrenched deep in the tumour microenvironment (TME). Treatments like CAR-T therapies have their fair share of challenges – since they are personalised, making them is time-consuming and demands expensive logistical and financial commitments. Checkpoint inhibitors have been more useful in eliciting immune responses against solid tumours, but tumours have also devised workarounds for them.

Enter CAR-M therapies. CAR macrophage therapy makes use of the existing capabilities of macrophages and boosts them with engineered chimeric antigen receptors (CARs). Macrophages are already integral elements of tumour mass, so they are able to sneak into the TME. CAR-M therapies are designed to infiltrate TMEs and then target tumours with precision.

Carisma Therapeutics is at the forefront of this new field. The company already has a lead pre-clinical candidate directed at HER2+ cancers. Their approach showcases promising outcomes, with improvements in overall survival rates. Though currently targeting a specific cancer subset, its implications may apply to a wider range of solid tumours. CAR-M’s possibilities for use against neurodegenerative diseases and inflammatory conditions also look promising. Exciting to have a new undercover agent in town! But shhhh, don’t tell the TME.
(Labiotech)

Pollution solutions. Yesterday, the Clean Air Fund released a report with a title that says it all: “From Pollution to Solution in Africa’s Cities”. The report analyses the health, economic, and environmental benefits of clean air in Africa’s 6 fastest growing cities.

Things are moving fast for Africa. Africa’s population is expected to almost double by mid-century. By 2060, more than 65% of people will reside in urban areas. And by the end of the century, Africa is likely to host five of the world’s 10 largest megacities. Rapid urbanisation will fuel its economies but also the insidious problem of air pollution.

The study focused on 6 rapidly expanding major African cities. In 2019, toxic air claimed more lives across Africa than tobacco, alcohol, motor vehicle accidents, and unsafe water combined. Air pollution across Accra, Cairo, Johannesburg, Lagos, Nairobi, and Yaoundé led to more than 56,400 premature deaths in 2022. If current trends in emissions from road traffic, industrial activities, power plants, biomass fuels, and waste mismanagement persist, air pollution’s financial toll in these big cities could surge 8x by 2040. Not to forget over one million premature deaths by the same year. If nothing changes, air pollution will cost the 6 cities an estimated $138 billion in premature deaths and worker absenteeism over the coming two decades. The report makes a case for investing in air pollution and climate change together. It offers a roadmap to avoid these horrific consequences while also creating opportunities for green economic growth.
(Clean Air Fund)

R&D

Snipping away at DNA. Did you know that CRISPR-Cas9’s OG function is a natural one, as part of microorganisms’ virus-fighting immune systems? Single-celled bacteria and archaea (nuclei-less single-celled organisms) use CRISPR systems to fight viruses called bacteriophages. Since we’ve found one lab tool for DNA editing in genomes, why not look here for more?

Researchers have developed an algorithm called FLSHclust to sort through millions of genomes in the hope that they will find rare new types of CRISPR systems for genome editing. They found about 130,000 genes associated in some way with CRISPR – 188 of these had never been seen before. Experiments in the lab revealed that CRISPR systems use various strategies to fight phages. They also revealed anti-CRISPR fragments of DNA that help the phages fight back. Crucially, the researchers found the code for an entirely unknown RNA-targeting CRISPR, which they’re calling type VII. Overall, the algorithm is a huge achievement because it will help researchers to look for other types of protein across species. Eventually, these could potentially be adopted for biological engineering or even to make diagnostic or research tools.
(Science)

The Kibble

Getting on your nerves. Have a literal itch that you want to scratch? Harvard Medical School scientists have found why exactly that is. It’s not inflammation, as previously thought. They’ve discovered that the common skin bacterium Staphylococcus aureus (which most people with atopic dermatitis have) releases a protease enzyme called V8. V8 activates a receptor on nerve fibres, which sends a message from the skin to the brain, fueling that need to scratch. When treated with the FDA-approved anti-clotting drug Vorapaxar, activation of the receptor was successfully blocked. The treatment also minimised skin damage. This discovery could be just the 🔑 needed to unlock new oral drugs and topical creams to address the annoying itches caused by conditions like atopic dermatitis, prurigo nodularis, and psoriasis.
(Cell)

Bottom Line

Sick planet, sick people. Over half the world’s population is not fully covered by essential health services; the climate crisis will only increase demand for these scarce resources. As climate-linked factors change infectious disease patterns, there is only so much progress that can be made on the public health front alone; simultaneous climate action and health advancements are necessary. On Wednesday, the World Bank and the Global Fund to Fight AIDS, Tuberculosis, and Malaria inked an MoU to support more effective, efficient, and sustainable financing to tackle health challenges in a time of climate change. The partners will advocate for increased financing and varied financial mechanisms. They will help localise health supply chains with support for sustainable manufacturing in Africa and LMICs elsewhere. Their work will also focus on stronger health systems, including better access to primary health care for the most vulnerable populations.
(Devex)

No biodiversity, no meds. Plants are pretty essential to our existence. We’re not just talking about the oxygen or food they provide us, but also the fact that they’re a source of medicinal compounds, both modern and traditional. In fact, over 40% of pharmaceutical formulations are derived from natural sources. Bio-inspired drugs include some for cancer, Parkinson’s, Alzheimer’s, and malaria.

But the way the Anthropocene has progressed so far, it doesn’t seem all of this biodiversity will be with us in the future. According to the World Economic Forum’s Global Risks Report 2023, biodiversity loss and ecosystem collapse are among the five leading risks facing the world over the coming decade. Biodiversity is dying out 500 times faster than before humans walked the Earth. Climate change and land-use change now threaten extinction for almost half of the world’s flowering plants. While some of these compounds can now be made synthetically, their original bio-inspirations (and potential future bio-inspirations) may be lost forever. This article outlines a few existing initiatives to nip the damage in the bud, like plant surveys and satellite and big data to monitor species and mitigate their extinction risk. But if we want to continue to see innovation in medicine, we should protect our sources.
(World Economic Forum)

Oh, and Gopal Nair doesn't want you to see this.