#015: A Review of Every Single Longevity Therapy in Clinical Trial Today. (PART 1)

Biogen rollercoaster. CRISPR Therapeutics patient death.

📡 In this edition of Longevity Marketcap Telemetry

  1. Notable Last Week

  2. Longevity Futures

  3. The 28+ Longevity Therapies Currently in Clinical Trials.

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

*Warning: Investing in biotech is risky!

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

Twitter: @realNathanCheng


📝 Notable Last Week(s)

What happened?!?!

  • FDA rejects Biogen’s (BIIB) Alzheimer drug, aducanumab. An outsider expert panel voted overwhelmingly against the evidence of aducanumab at the FDA hearing on Friday. Biogen’s stock had popped 40% days earlier on the release of the favourable FDA insider review briefing documents. However there were inklings trouble buried deep in the documents -- namely the comments by the statistical reviewer. Politics, public pressure, FDA insider bias all fuelled the controversy surrounding the approval process of this drug. The stock was halted all of Friday so Monday is likely to be an eye-opener.

    Alzheimer’s and other neurodegenerative diseases pose a formidable obstacle to radical life extension. 200+ failed trials in Alzheimer’s suggest we need a new paradigm for treating this disease: Aging. After all, 20 year olds don’t get Alzheimer’s disease.

  • CRISPR Therapeutics (CRSP) stock dives on news of patient death. The high-flying CRISPR gene-editing company co-founded by Emanuelle Charpentier released Phase 1 data regarding their CAR-T therapy for B-cell malignancies on Oct 21st, 2020. While 10 of the 11 patients responded well, one patient died from complications of the treatment (cytokine release + febrile neutropenia). The stock dropped 14% on the day but has since mostly recovered.

    CRISPR Therapeutics is one of the big 3 CRISPR gene editing plays, the others being Intellia (NTLA) and Editas (EDIT). However CRSP is the only CRISPR company with a regenerative medicine pipeline (for T1 diabetes).


📅 Longevity Futures

  • Master Investor Longevity Online Event November 10th, 2020 4PM (BST). Jim Mellon, billionaire and patron saint of longevity investing, is hosting an online webinar featuring many key individuals in the longevity science and investing space. Eric Verdin, Gregory Bailey, Alexandra Bause, Reason, Polina Mamoshina, will all be speaking. It’s free but make sure to register beforehand.


Every Single Longevity Therapy in Clinical Trials Today.

Anti-aging therapies are already being tested in human patients today. What strategies are being tried? Which ones are likely to succeed?

Note: I have compiled the clinical trial data from Part 1 and Part 2 into a Gantt chart + database + calendar. Enjoy!

Aging is a malleable biological process.

Scientists have been precisely turning the knobs of aging in model organisms since the 1990’s. Presently we have reached an inflection point: Therapies developed in the context of longevity science are being tested in human patients today.

Why the first longevity clinical trials are so important.

Currently there are 28+ anti-aging therapies in human clinical trials spanning a variety of strategies, targets, indications, companies, and modalities.

The trials are conducted by companies — private and public — but also universities and non-profit groups. There are also perhaps 100 more pre-clinical companies working on aging in addition to this effort.

If any one of the therapies in the first volley on the problem of aging achieve success — even if modest — it could trigger investor hype rivalling the biggest bubbles in history. The zero to one moment in human life extension will change everything.

As an investor in longevity biotechnology it is crucial to track every single anti-aging clinical trial because

  1. It gives you a full picture of the realized longevity therapeutics landscape.

  2. It gives you an idea of the timeline of the longevity revolution for capital deployment purposes. Example: If you can estimate the failure rate for longevity therapies (big if given their heterogeneity), the number of trials currently being conducted, and the growth rate in number of clinical trials, then you can forecast an approximate date for the first successful therapy.

Is it aging? Trial impact factor.

With the exception of maybe Nir Barzilai’s TAME metformin trial (not yet registered), none of the anti-aging therapies currently being tried directly use aging as their clinical endpoint.

Most trials instead measure a therapy’s efficacy with respect to a specific age-related disease rather than aging itself. Or sometimes the indication is a disease that can be treated with a tool developed from an aging perspective. This is because:

  1. The FDA does not recognize aging as an indication (yet).

  2. It is expensive to run trials that measure lifespan in humans.

  3. We don’t have have robust surrogate biomarkers for aging (yet).

  4. It is easier to demonstrate clinical significance in an age-related disease than aging itself.

Some trials will have more impact on igniting the longevity revolution than others. It all depends on the “sexiness” of the indication and the magnitude of clinical significance.

For example, it will be difficult for investors to get excited about Gensight’s allotopic mitochondrial DNA expression gene therapy for a rare genetic eye disease. The average investor doesn’t know how it relates to the fundamental SENS damage repair mtDNA category. In contrast, if the metformin-TAME trial demonstrates even a small 4% extension of lifespan that would be in the news everywhere.

The Great Anti-Aging Race.

So of the 28+ horses in the race for sparking the longevity biotech revolution, which ones are most likely to succeed and push the industry forward?

Let’s take a closer look at each anti-aging therapy currently being trialled.

1. Lorecivivint (STRIDES -1) - Samumed

Comments: Samumed is a private $12 billion+ regenerative medicine company that targets a number of diverse age-related diseases through a single pathway: The extensively-studied Wnt signalling pathway (stem cell differentiation and renewal). They are also one of the few anti-aging companies to make it to Phase 3.

Being able to treat many age-related disease through one fundamental approach is the holy grail of anti-aging science and longevity biotech. A success in Samumed’s broad Wnt signalling technology would validate anti-aging as a new paradigm for medicine.

Samumed is one of the “Big 3” broad pipeline companies in the anti-aging space, including Juvenescence and David Sinclair’s Life Biosciences. It is a shame they are not public yet. Though Frequency Therapeutics is doing something similar to regenerate inner ear hair cells through a GSK3 inhibitor / Wnt + Notch pathway.

2. UBX1325 - Unity Biotechnology (UBX)

Comments: Unity is back in the clinic with a 2nd trial: This time with a new senolytic drug and new pathway targeting various diseases of the eye. Success would validate the senescent cell approach and open a whole new class of drugs. Peter Thiel, Jeff Bezos, ARCH Venture Partners among others have invested in this company so there’s a lot of visibility.

Unity Biotechnology’s first trial, an osteoarthritis senolytic, failed in Phase 2, tanking the stock by 66%. We have little knowledge of why exactly the first trial failed — so the jury is still out on the senescent cell strategy in humans.

Reason and Jim Mellon criticized the trial design for its single dose injection, wishing they had chosen a systemic delivery instead. Unity’s new trial also uses a locally administered injection but the primary outcome (in Phase 2) should be less prone to placebo effects than their first trial.

3. Dasatinib + Quercetin - Mayo Clinic

Comments: One of the oldest senolytic therapies. Dasatinib is a cancer drug that is able to remove senescent cells in vitro, in mice, and likely in humans. The patent is owned by Bristol Myers Squibb until 2025.

Quercetin is a natural flavonoid found in kale and other plants that is believed to act as a senolytic by targeting the Bcl-xL apoptosis pathway.

Any successful trial, whether by a biotech company or a research non-profit like Mayo, will be pivotal in triggering a longevity revolution. After the patent expires on dasatinib there would be nothing to stop mass prescribing of this cheap therapy — if the trials show clinical significance. The evidence in mice and humans so far looks promising.

4. AKST-4290 - Alkahest (owned by Grifols)

Comments: Alkahest is the largest company actively pursuing the young blood factors / parabiosis strategy for aging. A success here would validate the idea that there are systemic factors in the blood that can modulated in order to affect aging broadly.

Alkahest is also trialling therapies for Parkinson’s, Alzheimer’s, inflammatory skin disease — using the small molecule drug Eotaxin inhibitor or a proprietary plasma fraction. Alkahest was recently fully acquired at a valuation of $265 million by Grifols (GRF), a Spanish blood bio supplies multinational corporation.

There are whispers of other players (Harold Katcher at Nugenics) with promising pre-clinical results entering this sub-niche of anti-aging. And of course Irina and Michael Conboy at UC Berkeley are also actively researching this space.

5. GRF6021 - Alkahest (owned by Grifols)

  • Status: Phase 2. Completion November 1, 2020.

  • Aging Target: Altered intercellular communication.

  • Indication: Parkinson’s Disease.

  • Endpoint: Improved cognitive function.

  • Primary / Secondary outcome measure: Change in Montreal Cognitive Assessment (MoCA) score.

  • Modality: Therapeutic proteins. Young blood plasma factors.

  • Mechanism: Intravenous infusion of a proprietary blood plasma fraction containing young blood factors identified by Alkahest’s chronokine screening.

  • Pre-clinical evidence:

  • Impact Factor: High.

Comments: Some of the first young blood factors and heterochronic parabiosis results in mice demonstrated rejuvenated neural tissue and improved cognition. A success here would validate the idea that there are systemic factors in the blood that affect aging and neurodegeneration.

6. TRIIM (somatropin, DHEA, metformin) - Intervene Immune

  • Status: Phase 2. Completion October 2022.

  • Aging Target: Cell loss. Immunosenesence.

  • Indication: Immunosenesence. (Thymic involution).

  • Endpoint: Improved immune function and age reversal.

  • Primary / Secondary outcome measure: Epigenetic aging (GrimAge). Thymus size and density, naive T cell function.

  • Modality: Peptide, small molecule drug, hormone.

  • Mechanism: Reverse immunosenesence by regrowing the thymus with somatropin (human growth hormone), suppress insulin effect with DHEA and metformin.

  • Pre-clinical evidence:

  • Impact Factor: High.

  • Trial link

Comments: This is the TRIIM-X trial, an expansion of the original TRIIM trial (HGH + DHEA + metformin only on small group of men). TRIIM-X is a larger cohort that includes women

Intervene Immune is Greg Fahy’s attempt to reverse aging and immunosenesence through thymic regeneration. It is one of the more notable trials as it measures the GrimAge methylation clock as a predictor of lifespan. The original TRIIM trial showed a reversal of 2.5 years of epigenetic age according to methylation clocks after 1 year of treatment.

Not sure how much these kinds of trials will move the needle on FDA approval of surrogate biomarkers for aging, but I am glad someone is trying. Profitability and patentability of the TRIIM combination treatment is going to be interesting. The three constituent compounds are already widely available and could be easily prescribed off-label.

7. DNL151 - Denali Therapeutics (DNLI)

Comments: Denali Therapeutics has a number of therapies targeting neurodegenerative diseases (Alzheimer’s, Parkinson’s) using different strategies.

Current treatments for Parkinson’s are based on increasing levels of dopamine, not treating the underlying biology. Clearing out intracellular aggregates may be key to overcoming neurodegenerative disease.

DNL151 in particular is interesting because it leverages the garbage collection function of the lysosomes inside cells to remove intracellular aggregates. The company is also developing a blood-brain-barrier drug delivery platform technology.

8. OpRegen - Lineage Cell Therapeutics (LCTX)

Comments: Lineage Cell Therapeutics (formerly BioTime) is a stem cell therapeutics company that is targeting dry AMD, spinal cord injury, and cancer using cells derived from allogeneic embryonic stem cells.

The stem cell therapy industry underwent a bubble in the late 90’s / early 2000’s as the hype of the science outstripped the actual implementation of therapies. 20 years later we are still waiting for a major regenerative stem cell therapy to be approved by the FDA. Mesoblast tried to get their foot through the door with Ryoncil — allogeneic mesenchymal cells that reduce inflammation — but it was ultimately rejected by the FDA.

All the current FDA-approved stem cell therapies are either cord blood-based and or blood and marrow cancer treatments. A major break through in stem cell therapy could signal the start of more sustainable growth in this sub-industry.

9. FX-322 - Frequency Therapeutics (FREQ)

Comments: Frequency Therapeutics has demonstrated the first sustained therapeutic improvement in human hearing loss. The initial sample size was relatively small but the breakthrough was promising nonetheless. The company also has a pre-clinical pipeline for regenerating neuron cell myelin to treat Parkinson’s Disease.

Frequency’s technology might have a limited applicability to other tissues despite what their marketing materials may claim. They currently only target specific progenitor cells that have express a Lgr5 marker.

10. GS010 (LUMEVOQ, Lenadogene nolparvovec) - Gensight Biologics (SIGHT.PA)

Comments: Gensight Biologics has demonstrated allotopic expression of mitochondrial genes in the cell nucleus to treat a rare genetic disease that causes blindness (LHON). Successful treatment of LHON is impressive in its own right but the real significance is how GS010’s therapeutic mechanism relates to aging.

Mitochondrial DNA is subject to harmful mutations as we age due to the reactive environment of the mitochondria. These mutations can lead to mitochondrial dysfunction and age-related diseases. Aubrey de Grey has suggested that the 13 (or 14) mitochondrial genes that encode for proteins must be protected and the best way to do this is to copy the genes into the cell nucleus. GS0101 is proof of concept that this can be done for at least one of the genes.

If Gensight’s allotopic gene therapy can be extended to all 14 mitochondrial proteins and delivered to the majority of the body (?) this would solve a major link in the aging process.

11. CB4211 - Cohbar (CWBR)

  • Status: Phase 1. Completion January 1, 2021.

  • Aging Target: Mitochondrial dysfunction.

  • Indication: Non-alcoholic fatty liver disease (NAFLD) / nonalcoholic steatohepatitis (NASH)

  • Endpoint: Safety first, afterwards probably liver fat or other surrogate.

  • Primary / Secondary outcome measure: Safety, adverse events, pharmacodynamics. Also: bodyweight, liver fat, and other biomarkers.

  • Modality: Peptide.

  • Mechanism: Analog of the natural MOTS-c mitochondrial peptide. Believed to regulate AMPK pathway and or insulin pathways. Subcutaneous injection.

  • Pre-clinical evidence:

  • Impact Factor: Medium.

  • Trial link

Comments: Cohbar is a company co-founded by Nir Barzilai. They are attempting to use naturally occurring mitochondrial peptides to treat various age-related diseases associated with mitochondrial dysfunction. Peptides are short chains of amino acids that can have modulatory effects on different pathways. In the case of CB4211, they are targeting the AMPK / insulin pathways.

The company itself is quite small but the approach is quite innovative.

12. RTB101 / Dactolisib - resTORbio x National Institute on Aging

Comments:

resTORbio is doing one last trial despite having merged with CAR-T therapy company Adicet Bio. The Phase 2 trial is in collaboration with the National Institute on Aging studying whether the RTB101 mTORC1 inhibitor is capable of protecting older adults from developing COVID-19 after exposure. mTORC1 inhibition is one of the most studied anti-aging pathways. The covid-19 angle increases the potential impact.

resTORbio already failed a Phase 3 trial in November 2019 for a similar indication (“respiratory illness / influenza”), which basically led to the salvage merger with Adicet Bio. The merger agreement stipulated that only shareholders of resTORbio will receive net proceeds from commercialization of RTB1010 — if any. So basically investing in Adicet won’t give you any exposure to the resTORbio pipeline. resTORbio’s website is also now defunct.

I don’t have much hope for this trial.

13. Elamipretide - Stealth BioTherapeutics (MITO)

Comments: Stealth BioTherapeutics has a number of planned trials targeting age-related diseases caused by mitochondrial dysfunction. Most use the peptide Elamipretide. Unfortunately, their first crack at treating Primary Mitochondrial Myopathy failed in December 2019 causing the stock tank. It is now down 90%.

Using aging science to develop therapies to treat non-aging diseases (i.e rare genetic diseases that have similar causes) has its pros and cons. On the one hand getting orphan drug designations can improve the economic calculus of running these trials. But on the other hand there can be a lot of other factors present in these genetic diseases aside from the common link that they share with general aging.

Stealth does however have a trial for age-related macular degeneration.

+ 15 more trials…

*This post is nearing the email truncation limit. I will post Part 2 later this week. Stay tuned!!