Image by alexraths at Depositphotos

Close to 250 oncology and CNS therapies are currently in development across the world, more than all other indications combined. In the US and much of the Western world endogenous and exogenous societal shifts, such as the use of tobacco, an aging demographic, and ever-growing obesity numbers are behind the patient-driven push to meet unmet needs in the oncology and CNS spaces.
2023 brought significant investment in oncology and CNS despite the market downturn. J.P. Morgan figures show that companies raised US$3 billion across 37 seed and Series A rounds, of which US$1.4 billion went to oncology-focused firms alone, nearly double the amount garnered by neuroscience biotechs. Oncology also led M&A investment, headlined by Pfizer’s US$43 billion acquisition of Seagen, and AbbVie tapping Immunogen for US$10 billion to expand its solid tumor portfolio. On the neuro side, BMS scooped up Karuna Therapeutics and its schizophrenia candidate KarXT, while AbbVie acquired Cereve Therapeutics.

Taking on a global killer
The global burden of cancer is growing. World Health Organization (WHO) data shows that about one in five people develop cancer in their lifetime, and approximately one in nine men and one in 12 women die from the disease. The disease – most common types being lungs, breast, and colorectal – is so spread globally that most people would likely know someone directly or indirectly affected by cancer. With cancer cases expected to grow by 77% at the turn of the century (up to 35 million in 2050, compared with 20 million in 2022) according to the UN’s International Agency for Research on Cancer, it appears obvious why the leading indication for scientists, investors and patients alike remains oncology. Indeed, oncology is forecast to be the largest market by indication, with a projected market volume of US$214.10 billion in 2024, according to Statista.

J&J recently shared a paper in which the drugmaker expressed eliminating cancer moved from an out-of-reach goal to one “within our grasp”. In 2023 alone, the leading oncology drugmaker presented new research in lung, bladder, and prostate cancers along with multiple myeloma, B-cell malignancies, and myeloid malignancies. In the US alone, the American Cancer Society projects over 2 million new cancer cases and 611,000 deaths in 2024, translating to 1,673 deaths per day. That said, survival rates have continued to improve in the country since the 1990s, following a blend of public policy initiatives targeting smoking, obesity, and pollution (the leading causes of cancer), and of course novel pharmaceutical therapies. Despite the pandemic causing a backlog in diagnosis and treatment, 2023 saw strides made in precision oncology, the “best new weapon to defeat cancer” according to Genetron Health CEO Sizhen Wang. The precision oncology approach identifies alterations in cells that may be driving the growth and spread of cancer, enabling the development of personalized treatment strategies.

Oncology is not ready to exit the spotlight. With patent cliffs looming, the trend of Big Pharma refurbishing its oncology pipelines is likely to sustain and strengthen. In the first half of 2024, BMS boosted its cancer pipeline by buying Mirati Therapeutics and completed the purchase of RayzeBio to enter the radiotherapeutics scene. AstraZeneca joined the radiopharmacy oncology waltz by announcing in March the takeover of Fusion Pharmaceuticals, while Novartis and J&J also bolstered their oncology pipelines. Gilead expanded its cancer cell therapy deal with biotech Arcellx late last year, with the collaboration now including two experimental drugs to treat multiple myeloma and will widen testing of one into lymphoma. Gilead can now co-develop and co-commercialize CART-ddBCM in the US. Arcellx’s CBO Aileen Fernandes shared: “Overall, oncology remains a high priority, as evidenced by recent financing trends, where approximately a quarter of recent funding has been directed towards oncology. This influx of capital is likely to bolster funding opportunities not only for oncology but also for the broader biotech sector.”

The ADC renaissance
After a true renaissance in 2023, an emerging class of biopharmaceutical drugs will undoubtedly keep getting attention in 2024 and beyond: Anti-Body Drug Conjugates (ADCs). Two decades after the approval of the first ADC, the established group of drugs are indeed late bloomers. The coming of age, materialized by Pfizer, AbbVie, and J&J’s acquisition of ADC developers since H2 2023 helped push tri-fold the value of ADC deals compared with 2022. As momentum continues in 2024, highlighted by J&J’s US$2 billion deal for Ambrx Biopharma, the significant investment underscores the rising value of a drug class that some advocates believe could eventually supplant certain traditional chemotherapy treatments. Currently, there are 11 approved ADCs in the US, with over half receiving FDA approval in 2019 or later.

The renaissance seen in pipelines is not due to an overnight success, but more to technical and scientific maturity, along with technological validation in recent years. ADCs got off to a bumpy start despite being labeled as “precision chemotherapy”. Indeed, identifying the optimal combination of antibody, linker molecule, and toxic payload presents challenges. ADC designers aim to replicate the characteristics of a standalone antibody, such as specificity, clearance profile, and toxicity, as closely as possible. However, they also intend to incorporate a potent payload without compromising the antibody's pharmacokinetics. Many drugs are hydrophobic, which can lead to aggregation and limited tissue penetration. In recent years, the success stories of drugs like T-DM1 (trastuzumab emtansine), Enhertu, Padcev, and Trovelvy have demonstrated the potential efficacy of ADCs in treating cancer, hence raising the class’ profile among investors and Big Pharma.

Innovation in scientists’ ability to engineer linkers and novel payloads means we are seeing improved applications in the ADC space. Among the biotechs developing ADCs for oncology targets, MBrace Therapeutics is leveraging validated linkers and payloads to mitigate risks associated with drug development. The biotech’s lead compound, MBRC-101, is an ADC targeting the EphA5 gene. MBRC-101 was manufactured using a conjugation platform with a cleavable linker and Monomethyl auristatin E (MMAE) payload with a Drug Antibody Ratio (DAR). MBrace’s co-founder and CEO Isan Chen recalled those technological prowesses: “Over the past two decades, there have been notable improvements in conjugation methods, linkers, and payloads enhancing the stability and efficacy of ADCs. The advancements in linker design play a crucial role in ensuring the targeted delivery of cytotoxic payloads to cancer cells while minimizing off-target effects.”

Neuroscience’s next frontier
For decades, researchers and scientists have been unsuccessful in their attempts to break the blood-brain barrier. The BBB, a selective semi-permeable membrane between the blood and the interstitium of the brain, allows cerebral blood vessels to regulate molecule and ion movement between the blood and the brain. Simply put, the system protects our brains from harmful chemicals. The issue is that molecules must cross that barrier and penetrate that system to treat neurological conditions such as Alzheimer’s and Parkinson’s. However, progress by researchers in 2023 bodes well for future breakthroughs.

The extreme difficulties associated with CNS drug development ought not to be understated. Under “normal conditions” (as defined by the NIH), the BBB prevents 98% of small molecules and 100% of large molecules from penetrating the brain. Making the BBB more permeable is therefore key, and researchers from Harvard Medical School might have made a pioneering step in that direction. In July 2023, researchers identified a gene expressed in neurons that when mutated increases the permeability of specific regions of the blood-brain barrier. These findings could assist scientists in regulating the blood-brain barrier, which is vital for delivering drugs to the central nervous system or addressing damage caused by neurodegenerative diseases.

The partnership between academia and the private sector might be stronger in neuroscientific disciplines than for any other indications to try and overcome the BBB. According to a recent Deloitte report focused on sizing the brain, the neuroscience diagnostic market is primarily driven by medical imaging and next-generation sequencing technologies. As such, in 2023, a decade after the launch of the Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) initiative, MIT and UCI received millions in NIH grants to develop the connections between the 86 billion neurons that form more than 100 trillion connections in our brains.

The dementia landscape evolves
Newly discovered treatments that have the potential to reverse Alzheimer’s disease (AD) signs or remove toxic proteins from the brain are sustaining enthusiasm in the CNS market. In August 2023, the FDA approved Leqembi, a disease-modifying drug for Alzheimer’s, the second only to address the progression of the disease. Leqembi functions by targeting amyloid beta, the primary component of the amyloid plaques present in the brains of Alzheimer's patients, impacting memory and cognitive functions. It labels these plaques for elimination by the body's immune system, thereby slowing the progression of Alzheimer's symptoms. Vaccines are among the treatments bringing hope to patients and investors. Companies like Elil Lilly and Prothena have expressed renewed interest as vaccines are easier to administrate and less frequent in dosing (Leqembi requires two injections per month). Firms like Prothena, AC Immune, and Vaxxinity all saw their AD-focused programs making strides in 2023. The efforts, however, continue to encounter setbacks. In January, Biogen dropped its controversial Alzheimer drug Aduhelm along with an FDA-ordered clinical trial deemed by a certain FDA regulator “the worst approval decision that the FDA has made that I can remember.”

Now that Leqembi has proved that AD treatment works, the next step for drugmakers and biotechs will be developing shots that will not only generate response but also keep inflammation in control. Indeed, treating neurogenerative diseases like Alzheimers or Parkinsons without side effects is a complex endeavor. The approval of Eisai and Biogen’s Leqembi marked a pioneering moment for the approval of an early-treatment Alzheimer’s drug on the US market. Yet, in terms of sales and adoption, the drug has been off to a slow start, notably due to potential side effects that include frequent infections, brain swelling, and bleeding. In a third-quarter earnings presentation, Eisai reported the drug had reached only 2,000 patients, below target as it aimed for 10,000 by the end of 2024. To mitigate side effects,which, like in the case of cancer, are sometimes worse for the patient than the disease itself, Aphios decided to go beyond what was available on the market and develop APH-1104, a novel α-secretase modulator and potential AD therapeutic. “This will not only help delay or prevent symptoms from becoming worse but will also increase memory by the regeneration of synapses or synaptogenesis,” said the company’s CEO, Trevor P. Castor.

Crossing the blood-brain barrier is a challenge that pertains to a natural dimension as the system was designed as part of our species’ evolution. And like anytime humanity attempts to play with Nature, results are likely to take years to materialize. Nonetheless, Big Pharma, VC, and biotechs are increasingly pooling capital to smuggle drugs into the brain. Investment in the neuroscience market is perhaps more needed than ever: Beyond brain disorders being the leading cause of disability worldwide, an aging population (the number of people expected to live with Alzheimer’s in the US is forecasted to more than double between now and 2050 to 13 million) dozens of psychological studies have emerged post-COVID-19 showcasing that the unprecedented stress test negatively impacted brain disorders across the world.