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Observations #36
A set of ideas and observations from a week’s worth of work analyzing businesses and technologies.
HSC therapies
Hematopoietic stem cells (HSC) are the source of blood cells from lymphocytes, red blood cells, monocytes among others. HSCs come in two lineages:
Lymphoid - encoding lymphocytes and NK cells
Myeloid - encoding red blood cells, macrophages, and more (this is a large opportunity to make more precise medicines for myeloid-derived diseases since this lineage encodes very essential cells that can lead to toxicity for myeloid-targeting medicines)
Over the last 6 decades, HSC transplants and medicines have become essential to cure several diseases from cancer to blood disorders. The first successful bone marrow derived HSC transplant was performed in the 1950s by E. Donnall Thomas at Fred Hutchinson Cancer Research Center; he won a Nobel Prize for this. Thomas infused bone marrow cells to repopulate the bone marrow of the patient to produce new blood cells. In 1961, the HSC was defined and characterized by two features: (1) self-renewal and (2) can produce different types of blood cells. Simply, resetting the immune system with an HSC transplant is incredibly powerful and curative. The procedure can be divided into two categories:
Allogeneic - hematopoietic stem and progenitor cells (HSPC) are sourced from a healthy donor and used to re-populate another patient’s hematopoietic and immune systems (~40% of transplants)
Autologous - the patient's own HSPC are used for a transplant (~60%)
To ensure the transplant engrafts and long-term durability for the patient, the material sourced must have HSCs. Finding healthy and immune compatible HSCs is another issue. As well as the conditioning regimens that are required to reset the immune system and improve the odds of a successful HSC engraftment. As a result, HSC transplants have pretty high mortality rates, which limits its uses in non-malignant/non-life-threatening diseases. However, if these issues can be solved, HSCs have the potential to create long-term cures for immune-related disease. For example, checkpoint inhibitors and CAR-T cell therapies have issues with response rates and sometimes safety. Combining these medicines with HSCs have the potential to lead to strong response rates with durable effects:
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3901057/
However, HSCs face several barriers from becoming more widely used:
HSCs are unable to proliferate and differentiate in vitro. There is a high need for new sources of healthy and immune-compatible HSCs. Umbilical cord blood is a source of a large number of HSCs but has high costs and long timelines for collection, enrichment, HLA typing, and more.
Then determining how many HSCs are in a transplant is pretty difficult. Around 1 out of 10,000 cells in the bone marrow are thought to be HSCs with that number becoming 1 in 100,000 for blood. Developing better biomarkers (i.e. CD34) and sorting tools are needed.
HLA matching is important before a HSC transplant; however, there are low HLA matching rates in the human population. Finding ways to enable successful transplants without HLA matching is important or creating large registries to make matching easier. Figuring this out with minimizing/eliminating graft-versus-host-disease (GvHD) is important. GvHD is probably the biggest barrier for HSCs.
Multiple infusions are often required that can lead to infusion reactions, late toxicities, and relapse in patients.
Expanding and collecting HSCs; developing better harvesting methods and mobilization drugs is valuable.
Engineering HSCs with gene transfers (i.e. viral) and editing may expand the capabilities of an HSC. Ex vivo methods are limited by the small proportion of HSCs in a bone marrow population.
Conditioning regimens like chemotherapy and radiation are used to clear out a patient's blood system to improve the probability of an HSC transplant (i.e. prevent GvHD). Antibodies against targets like CD47 and CD45 have been shown to improve engraftment with less toxicity.
Ultimately, if these problems are solved, HSC medicines have the potential to cure, or at least improve patient mortality rates substantially, most diseases driven by the human immune system.
Soliris - drugs that are their own pipelines
Soliris (eculizumab) is an antibody complement inhibitor that has transformed the lives of patients with ultra-orphan diseases and built up Alexion as an iconic drug development company. Soliris is an example of a drug that is its own pipeline: with 4 large-scale successes over the last ~2 decades and 9 failures.
In 2007, Soliris was approved to treat paroxysmal nocturnal hemoglobinuria (PNH) after 4 suspended trials. In 2011, the FDA approved Soliris to treat atypical hemolytic uremic syndrome (aHUS). The drug was the first approved medicine for either of these ultra-rare orphan diseases. Overtime, Soliris received approval to treat adult patients with generalized myasthenia gravis (MG) and neuromyelitis optica (NMO). Alexion has created other complement inhibitors and still is working on expanding the use of Soliris across more indications. What has enabled Soliris to become a drug that is its own pipeline is the focus on complement that drives the pathology for many immunological diseases.
The founders of Alexion were not only pioneers in validating the ultra-rare orphan disease business model but set a great example of how to position one drug as its own pipeline. The company had failures in larger indications like RA and lupus. By focusing on ultra-rare diseases that have lower standard-of-cares but often have trouble with patient recruitment enabled Alexion to build a franchise. Soliris is a very useful case study of how one drug can treat more than one condition expanding its label of time. This type of model not only helps more and more patients but creates a very efficient drug development business: it becomes more about clinical execution than finding the next blockbuster.
What is Life? cont.
In What is Life?, Chapter 2 (The Hereditary Mechanism) centers around understanding hereditary information. Across chapter 2 and 3, Schrödinger concludes that a gene stores this information and must be small (to have diversity) and have long-term stability (to be transferred across generations).
For Schrödinger, for these two properties to exist, “an organism and all the biologically relevant processes that it experiences must have an extremely ‘many-atomic’ structure and must be safeguarded against haphazard, ‘single-atomic’ events attaining too great importance.” As a result, a chromosome is “code-script” that contains the information encoding for the developmental pathway of an organism robust against single atom changes. Chromosomes “are architect’s plan and builder’s craft – in one.”
Chapter 2 is a setup for the next chapter (Mutations). But Schrödinger’s intuition for genes is pretty amazing for its time.