Oncology and CNS Lead the Way in Drug Discovery and Development

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.