#014: How to Modulate Human Biology

Biotech Modality Cheat Sheet. Capital Markets Panel @ Metabesity 2020. Calico's first trial. Top finds.

📡 In this edition of Longevity Marketcap Telemetry:

1. Notable last week.

2. Longevity Futures

3. Notes from VC Panel @ Metabesity 2020

4. A Cheat Sheet for Biotech Modalities

5. Technical Analysis

*Special Note 🎉🎉🎉: We recently broke above 100 newsletter subscribers (132 to be exact) with a strong increase last week. We are just getting started. The more awareness we can raise about longevity biotechnology, the faster we can end aging. Thank you to all you early adopters!

-Nathan Cheng // LongevityMarketcap.com // LongevityList.com // Biohackstack.com

*Disclaimer: None of this should be taken as financial advice. It is for educational purposes only.

*Warning: Investing in biotech is risky!

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📝 Notable Last Week

What happened?!

• Google’s Calico enters the clinic for the first time. 7 years after inception, Google’s secretive anti-aging moonshot, Calico, started a Phase 1 trial (in collaboration with AbbVie) targeting solid tumours. Not much is known about the pipeline other than that it is PD-1 checkpoint inhibitor — so another immunotherapy cancer play.

  Longevity Twitter was unimpressed — but perhaps the innovation here could be how the drug was discovered and designed (AI techniques no doubt) rather than what kind of drug/

• Insilico Medicine partners with Taisho Pharmaceutical for senescent cell pipeline. Alex Zhavoronkov’s Insilico Medicine is in the news again — this time with a partnership with Japan’s Taisho Pharmaceutical (TYO:4581). Taisho will use Insilico’s AI drug discovery platform to find new molecules to target senescent cells. Taisho also has other ties to the longevity industry: They recently licensed a hypoxia pathway drug to Kristen Fortney’s BioAge Labs. I will be adding Taisho to the Longevity Marketcap list shortly.

• Vertex Pharmaceutical stock drops 20% on news of halted trial for rare lung/liver disease. Vertex is best known for their monopoly on cystic fibrosis, having developed four successful small molecule protein modulator drugs. The company was working on a drug to treat AATD (Alpha-1 antitrypsin deficiency), a rare lung/liver disease with a similar mechanism as cystic fibrosis. Unfortunately, Vertex announced it was discontinuing the drug on reports of liver toxicity in their Phase 2 trial. Vertex’s stock dropped 20% on the news.

  Gene-editing company Beam Therapeutics (BEAM) also has a pipeline to treat AATD. BEAM was up 16% on the news.

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📅 Longevity Futures

• George Church webinar discussion on aging 12PM (PST) October 26, 2020. George Church is professor of genetics at Harvard and one of the pioneers in the field of gene sequencing and synthetic biology. He is also the co-founder of several different biotech companies including eGenesis (xenotransplantation), Editas (CRISPR gene editing), and Rejuvenate Bio (life extension for dogs). I’m not going to miss this one.

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⛏️ Top Finds

Too good to not share.

• Laura Deming (The Longevity Fund) published a blog post on tips for newcomer’s in the biotech field. Deming lays out concepts and resources that will help new investors and startup founders navigate the field. She recommends three things:

  1. Understand all the different ways we can modulate human biology (small molecule drugs vs cellular therapies vs monoclonal antibodies vs genetic therapy, vs nucleic acids, etc)

  2. Understand the financial models that biotech companies and VCs use to calculate investment returns.

  3. “Don't take anyone's word for it that we can change human longevity with our current tools - prove or disprove this for yourself.”

• Bay Bridge Bio. This is a data-driven website by biotech consultant Richard Murphey. It contains biotech funding and exits stats, valuation models, startup database, biotech startup course, and an insightful blog.

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Notes from Capital Markets Panel @ Metabesity 2020

The Metabesity 2020 conference took place last week. Here are my notes from one of the more relevant panel discussions on longevity capital markets, featuring Laura Deming (The Longevity Fund).

1. COVID: Company development is accelerating. More money in Biotech.

• Company development speed has 2x’d over the past year, according to Laura Deming. She believes that the number of higher quality founders is contributing to this acceleration. To me this is a clear indication that the industry is maturing. More best practices and biotech startup infrastructure will streamline company development.

• Biotech IPOs and SPACs are booming, giving access to a more diverse class of investors.

2. Longevity Biotech vs Traditional Biotech

• Many longevity biotechnology companies in the past did not market themselves as anti-aging companies. They instead market themselves as targeting some specific age-related disease.

• Today, more longevity companies are doing away with the “normal biotech” disguise and branding themselves as anti-aging companies.

• James Peyer (Cambrian Biopharma), believes that longevity biotech and traditional biotech are still very similar in the beginning stages. It isn’t till Phase 2 trials that longevity companies can differentiate themselves more for applications in preventative medicine.

3. Longevity and Biotech VCs expect 20% - 30% IRR

• IRR (Internal Rate of Return) is defined as the discount rate that makes the Net Present Value of an investment equal to zero. IRR is a way to measure an annualized return rate in a venture capital fund.

• The panelists at Metabesity were asked what kind of IRR benchmarks longevity biotech investor were expecting. Here were their answers:

  • Laura Deming: 25% IRR

  • James Peyer: 25% - 30% IRR

  • Kris Verburgh: 20% IRR

• 20 - 30% is a pretty typical expected IRRs even for non-longevity biotech VC funds. According to a Cambridge Associates Report, the average VC Fund IRR from 2010 - 2016 vintages was 21.9%. Interestingly, the ARK Genomics Revolution ETF also has a 22% CAGR since inception in 2014 — interpret that as you wish.

4. Too many bad companies

• The panel was divided over the question of whether there were too many companies getting into the field.

• Laura Deming and James Peyer both believed there were too many bad companies. In particular Deming believed there was an over-reliance on the “Hallmarks of Aging” for treatment strategies — especially since the underlying biology of aging is still unknown.

5. The Future of Longevity Biotech

• Laura Deming believes longevity needs its first major success to really start attracting more capital to the industry. As an example, Xcyte attempted to engineer T-cells for cancer in the 2000s but it wasn’t until a decade later that Juno Therapeutics’ success revolutionized the field. Now CAR-T is one of the hottest areas to invest in biotech.

• Most of the longevity VCs on the panel believe that the first major success will come within the next 10 years.

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How to Modulate Human Biology: A Biotech Modality Cheat Sheet.

For the newcomers to biotechnology (myself included), and in following the advice in Laura Deming’s latest blog post, I have created a cheat sheet comparison of the most common biotech therapeutic modalities. I feel it is necessary to familiarize yourself with all the major tools in the biotech tool kit as an investor or potential founder.

But remember: Don’t take any of this as gospel — rules can be broken.

There are other modalities not covered here and many more that will be developed in the future that might be used to modulate the biology of aging.

For regulatory purposes the FDA divides therapies into two categories:

1. small molecule drugs (chemicals)

2. biologics (products from a biological system), including:

   • therapeutic proteins

   • peptides

   • monoclonal antibodies

   • fusion proteins

   • nucleic acids (DNA, RNA)

   • gene therapies

   • cell therapies

For a general overview of the differences between small molecule drugs and biologics see this article.

Let’s take a look at the main specs and differences of each modality and how they apply to longevity biotechnology:

Note on units: 1 kiloDalton (1 kDa) is roughly the same mass as 1000 hydrogen atoms.

1. Small Molecule Drugs

• Example: Aspirin. (2-Acetoxybenzoic acid)

• What is it: A molecule made of a small number of atoms.

• Size: < 100 atoms.

• Weight: < 1 kDa

• Properties: Chemically and thermally stable. Long shelf-life.

• Mechanism: Binding to proteins to modulate their function

• Use case: Many. Small size means easy to enter the cell or cross blood brain barrier.

• Delivery: Oral (most convenient) but other invasive methods also possible.

• Elimination: Filtered by (off-target) organs like kidney and liver. Generally short half-life

• Safety: Off-target effects common. toxicity.

• Manufacture: Chemical synthesis.

• Example Companies: Unity Biotechnology, resTORbio

2. Therapeutic proteins (non-antibody)

• Example: Factor VIII

• What is it: A large molecule made of many amino acids

• Size: More than 50 amino acids, more than 1,000 atoms

• Weight: > 10 kDA

• Properties: Heat sensitive, polar, unstable

• Mechanism: Replacing deficient proteins, modulating a pathway, transport, or adding novel functions. Basically doing protein things.

• Use case: Many. usually interacts with cell surface or extracellular molecules or used as transport

• Delivery: Invasive. Too large for oral delivery.

• Elimination: Breakdown by systemic enzymes, proteins. half-life depends on protein binding efficiency, can be short.

• Safety: High selectivity, generally safe. But possible immunogenicity.

• Manufacture: Recombinant DNA or harvested from natural sources.

• Example Companies: Alkahest.

3. Peptides

• Example: Angiotensin II

• What is it: A short chain of amino acids. Sometimes name ends in “-ide”

• Size: Less than 50 - 100 amino acids. Less than 2000 atoms

• Weight: ~ 1 - 10 kDa

• Properties: Heat sensitive, polar, unstable, susceptible to aggregation

• Mechanism: Mimics natural ligands (biomolecule complexes that interact with receptors)

• Use case: Many. Usually targeting a specific receptor.

• Delivery: Oral is possible but difficult. Possible to permeate cell membrane but difficult.

• Elimination: Breakdown by systemic enzymes. Generally short half-life

• Safety: Relatively safe. Possible immunogenicity.

• Manufacture: Chemical synthesis.

• Example Companies: Cohbar

4. Monoclonal Antibodies

• Example: Humira (Adalimumab)

• What is it: Identical Y-shaped proteins that binds to a specific antigen. Important in immune function. Name ends in “-mab”

• Size: ~ 25,000 atoms

• Weight: ~ 150 kDa

• Properties: Fairly stable compared to smaller proteins, heat sensitive

• Mechanism: Modulating the immune system in various ways. Flagging cancer cells, inactivating overactive immune cells, binding to signalling proteins involved in cancer or autoimmune disease, inhibit proteins that help cancer cells evade immune system (checkpoint inhibitors), etc

• Use case: Mostly for cancer and autoimmune disease. But other use cases possible.

• Delivery: Invasive.

• Elimination: Long half-life (several days to weeks). Antibodies protected from breakdown when cycling in and out of cells

• Safety: High selectivity, low toxicity. Possible cancer or infection risk when modulating immune system and cancer cells.

• Manufacture: Usually expressed in engineered mice. Scaled production in-vitro using hybridomas.

• Example Companies: Genentech, AbbVie, etc.

5. Nucleic Acids

• Example: Kynamro (Mipomersen)

• What is it: Short strands of single or double stranded RNA that silences gene expression. Antisense Short Oligonucleotides (ASO) and Small Interfering RNA (siRNA). name ends in “-sen” or “-ran”.

• Size: ~ 8 - 100 base pairs

• Weight: ~ 3 - 30 kDa

• Properties: Charged, unstable in biological environments, heat sensitive. Can be chemically modified to be more stable.

• Mechanism: ASO: Single stranded complementary RNA binds to specific mRNA to stop translation of bad proteins.
  siRNA: Cellular proteins cleave double-stranded RNA into fragments, split RNA into single anti-sense strand, which binds to or cleaves complementary mRNA.

• Use case: Genetic diseases, silence expression of disease proteins

• Delivery: Invasive. Cell intake via endocytosis.

• Elimination: Half-life can be several weeks in chemically enhanced nucleic acids. Filtered by liver and kidneys.

• Safety: Risk of off-target effects. Targeting wrong cells. Toxicity.

• Manufacture: Chemical synthesis.

• Example Companies: Ionis Therapeutics, Alnylam Pharmaceuticals

5. Gene Therapies

• Example: Luxturna (Voretigene neparvovec)

• What is it: Inserting genes into cells, editing or removing cell genes. Variety of different methods: Viral vectors, chemical vectors, CRISPR, TALENS, etc. Can be in vivo or in vitro.

• Size: ~10 - 100 nm. Transgenes : ~ 5 - 10 kilobases. (viral vectors)

• Weight: ~ 1,000 kDa - 100,000 kDa (For viral vectors)

• Properties: Viral vectors: Heat sensitive, easily degraded. Short-shelf life

• Mechanism: Viral vectors: Inactivated virus, usually AAV or lentivirus, is engineered to insert specific genes into cells to correct missing or defective genes or confer novel function. Other techniques (CRISPR, etc) available. Can be in vivo or in vitro + cell transplantation.

• Use case: Genetic diseases, engineering immune cells to fight cancer.

• Delivery: Invasive.

• Elimination: Inserted genes can be transient or sustained. Viral vectors have short half-life.

• Safety: Off-target risk. Immunogenicity. Cancer risk. Viral vector toxicity. Risk of viral vector regaining replicative function.

• Manufacture: Cell cultures. Produced using recombinant DNA techniques and engineered packaging cell lines in vitro (viral vectors).

• Example Companies: Spark Therapeutics, Juno Therapeutics.

6. Cell Therapies

• Example: Ryoncil (Remestemcel-l)

• What is it: Cells (usually human). Can be autologous or allogenic. Can be natural or genetically engineered.

• Size: ~ 100 trillion atoms

• Weight: ~ 1 trillion kDa

• Properties: Limited shelf life, needs to be frozen. in vivo stability depends on viability of cells.

• Mechanism: Replace lost or defective cells, transplant cells with novel function, or introduce cells that secrete therapeutic factors in-vivo.

• Use case: Regenerative medicine, blood or marrow cancers, cancer (CAR-T), anti-inflammatory secretory factors (remestemcel-l)

• Delivery: Invasive. Injection, grafting, implantation.

• Elimination: Depends on viability of cells.

• Safety: Immunogenicity risk (allogenic cells and engineered autologous cells). Cancer risk (stem cells).

• Manufacture: Donor cells culture-expanded (allogenic cell therapy). Autologous therapies engineered from patient cells ex vivo.

• Example Companies: Mesoblast, AgeX Therapeutics, Lineage Cell Therapeutics, Juno Therapeutics.

General Market and Regulatory Considerations

• Small molecules make up the majority of FDA approved therapies.

• However the majority of top selling drugs are biologics (monoclonal antibodies in particular).

• There are only 18 FDA approved gene therapies or cell therapies — and many are just umbilical cord stem cell related.

• Only three gene therapies have been approved by the FDA to date.

• Most FDA-approved cell therapies are related to blood / marrow cancer therapies.

Which therapeutic modalities are used in anti-aging?

• The majority of the publicly-traded longevity companies use small molecule drugs or cell therapies.

• But there are many anti-aging companies pursuing modalities outside of small molecules or cell therapies:

  • Gensight Biologics’ Lumevoq seems capable of correcting a rare mitochondrial DNA mutation by expressing the mitochondrial genes inside the cell nucleus. mtDNA mutations build up with age so this modality is crucial.

  • Oisin Biotechnologies is developing a lipid-protein nanoparticle gene therapy to remove senescent cells.

  • Turn Biotechnologies is using mRNA to deliver reprogramming factors to cells.

  • Repair Biotechnologies (founded by Reason) is developing a gene therapy to target cholesterol buildup and thymic involution.

  • Alkahest is developing therapeutic proteins and plasma fractions based on studies of how factors in blood change with age.

  • Cohbar is a company co-founded by Nir Barzilia that is attempting to use mitochondrial peptides to treat disease.

  • Cellvie is developing therapeutic mitochondrial transfer to augment cells with healthy mitochondria.

• Other developing modalities for anti-aging: xenotransplantation, 3D bioprinting, multi-specifics, PROTACs, etc.

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Technical Analysis

This is the section of the newsletter where we analyze price movement of specific stocks — mostly with TD Sequential momentum indicators.

Vertex Pharmaceutical (VRTX)

Daily chart: News of Vertex’s failed AATD drug sent the stock down 20% and it appears to be trending lower. There may be a nice TD 9 Buy signal coming early next week, maybe Tuesday. Could be a nice short term pop at the least.

This stock is in passive ETFs and major indices (SPY, QQQ, IBB) so there should be some buying support eventually. The price is currently back to March levels. Ark Invest has been buying the dip in the past few days.

Mesoblast (MESO)

Daily Chart: This Australian stem cell therapy stock is still down 43% since the FDA rejected Ryoncil (remestemcel-l) for treatment of pediatric graft vs host disease. Downside momentum looks like it could be exhausted — at least temporarily. We are sitting just around the 200 day SMA. Weekly chart is also showing signs of possible momentum reversal, TD is 7.

My only hesitation is the huge gap up in April and the multiple touches on the resistance level around $11.

Repare Therapeutics (RPTX)

This precision oncology stock showed up on my radar when I saw Ark Invest had recently added it to their Genomics ETF (ARKG). The stock was down 30% with a consolidation after a TD 9 Daily buy signal. It’s unfortunate that the price already popped 11% earlier today but there could be more upside ahead. I’m watching this one.