This work was financially supported
by Alexey Gubarev and the Haxus Foundation


How investments in biotech
can extend your lifespan

Part 1: intercellular matrix

Dora Bataeva
Author
Nastya Egorova
Editor
Misha Batin
Ideologist of the project
Irisha Efremova
Illustrator
Nodar Lakhuti
Translated this text from Russian to English
How did we compile this list?
What are these companies? Why these, exactly? Where did we start from?

We started our work with the list of known biomarkers of aging, that, in our view, are important to maintain in a certain range of values - this will help maintain health, improve well-being and achieve maximum life expectancy. We chose our markers as optimal predictors of increasing the likelihood of death.

Today, there are several panels (lists) of biomarkers of aging, ours being one of them - Open Longevity. We constantly monitor and analyse other approaches to diagnostics, but this text was based on ours.


We selected several markers from the panel, which involve the same processes: inflammation, synthesis, and degradation of the extracellular matrix. And then examined the diseases associated with them.

Essentially, these are extreme cases of metabolic pathway breakdowns that accumulate with age (although the diseases discussed in the article are not always age-related). Having compiled a list of the diseases and processes that interest us, we began to look for biotechnological companies that develop relevant therapies.


These companies, unknowingly, or perhaps quite intentionally, are creating what can become part of a global therapy for aging.

For example
Diabetes, a severe case of insulin resistance, as well as fibrosis and some forms of cancer are extreme cases of an imbalance in the synthesis and degradation of the extracellular matrix. We do not claim that the treatment of diabetes, cancer, and fibrosis can help us stay young, but looking in that direction can be helpful, nonetheless.

Another reason to pay attention to these companies is an economic one. Many of the drugs we reviewed have received Fast Track FDA status or Orphan Drug Designation status.

To develop a unique orphan drug and subsequently use it for a wider range of diseases and introduce it to a wider market is a good strategy from an economic point of view.

Orphan diseases are diseases that so few people suffer from that the development of drugs (the so-called orphan drugs) will most likely not pay off and will not bring profit. At the same time, thousands of people suffer from orphan diseases, and they do need help. The state supports the development of orphan drugs by accelerating the process of issuing permits and issuing grants.
Fast Track is designed to facilitate the development of drugs that treat serious or life-threatening conditions and have the potential to address unmet medical needs. The Fast Track status can be requested by the developer from the FDA at any stage of drug development. If the FDA approves the status, then developers can communicate with the FDA more often than when developing a conventional drug, and questions and problems are resolved more quickly. This often leads to the drug being approved by the FDA faster and becoming available to patients sooner.
For example
Rituxan [1, 2] could be one example. The drug was developed jointly by Roche and Biogen and was intended to treat two rare diseases: chronic lymphocytic leukaemia and non-Hodgkin's lymphoma. But later it turned out to be effective for the treatment of rheumatoid arthritis, which is not an orphan disease. Rituxan sales revenue brought Roche nearly $ 8 billion in 2017 and $ 1.4 billion the same year to Biogen.

...by buying shares of such a company you buy a chance to extend your own life.
Obviously, the age-dependent diseases market is especially attractive: we all age, so the products of these companies will always find their consumers.

But there is another reason: by buying shares of such a company you buy a chance to extend your own life.

Aging is an invincible monster. At least, it has always been so, and sometimes this thought paralyzes us. But if you think about it, you and we potentially have many allies—almost all of humanity.


One of the features of age-dependent diseases is their prevalence. For example, in the United States, more than 25% of people over 65 have diabetes [X].

Beyond there being a lot of patients, these diseases are often fatal . In 2016, of the nearly 56.9 million deaths worldwide, 16.2 million were caused by coronary heart diseases and strokes. 3 million people died from chronic obstructive pulmonary disease (COPD) and 1.6 million from diabetes. We have listed only a few age-related diseases, and yet they account for 36.6% of all deaths in the world. And there are also oncological diseases—most of them are also age-related.


If all people joined their efforts and invested in the treatment of diseases that they themselves have, it is possible that medicines could be discovered faster. What will the world look like in which there are no age-dependent diseases? Such a picture may seem a fantasy, but think about universal vaccination, thanks to which people around the world began to live to adulthood instead of dying in childhood.


Financial analysis and aging diagnostics - such a strategy seems optimal to us.
How to choose a company to invest in? From the point of view of potential profitability, we need to predict its capability of bringing the drug to the market. Financial support from other companies is a good sign. Late stage of clinical trials is a good sign, too.

Yet from the point of view of health you also need to assess your risks to develop age-specific diseases. Which diseases are most likely to worsen your quality of life or even become the cause of your death? Is there currently an affordable drug on the market, or is it critically important to develop one and bring it into clinical practice?


Diagnostics of aging is of help here (molecular biological parameters of blood and more that reflect the state of health and risks of age-related diseases at the given moment), family history of diseases, genetic testing... Of course, there is no guarantee of success, but we consider this strategy to be very logical, as it increases the chances of prolonging a healthy period of life and survival in general.


Read more about diagnostic methods here.

So, at last, let's get on with the list of companies which are interesting from the point of view of investments, both for those who just invest in biotechnology, and those who have already been tested for a panel of biomarkers and detected developing health problems.


This article marks the beginning of our analytical work. In the future, we will adjust and improve our strategy. Leave comments, write reviews, and share with us your opinions and information on the state of the market of biotechnological companies. Let's create the list of really promising companies together.

Financial analysis and aging diagnostics - such a strategy seems optimal to us.


This article does not contain any direct recommendations on buying any listed stocks.

Fibrocell Technologies Inc.

Fibrocell Technologies Inc. specialises in cell and gene therapy for skin and connective tissue diseases.


The company's history goes back to 1995. Fibrocell had another name then - Isolagen Technologies - and specialised in development and production of anti-wrinkle medication Laviv. The medication was based on the patient's own cells; fibroblast cells were taken from the patient, cultured ("multiplied") and injected intracutaneously into the nasolabial folds of the patient. Laviv was approved by the FDA in 2011 for cosmetic injections. The drug passed two Phase II clinical trials and five Phase III clinical trials.

Laviv can still be found on the market, but its effect is considered "light, natural" (for example, acne scars are indeed smoothed, but deep and pronounced scars cannot be overcome). The cost is high: $ 2,400 per procedure. A patient needs to wait for about three months until the cells of the drug multiply and reach a sufficient number. Moreover, in order for the effect to be noticeable, several injections are needed - usually three, with a break of six weeks.

Apparently, Laviv did not became popular, and to not to lose the investment it was needed to find another application for the drug, more important than the treatment of nasolabial folds. Fibrocell tried to repurpose Laviv for treatment for scarring of the vocal cords, which leads to chronic or severe dysphonia, but Phase II clinical trials were unsuccessful. In 2016, Fibrocell stopped working on Laviv, cutting 24 jobs. Now the company has 23 employees.

In the same year, Fibrocell and Intrexon Corporation (NASDAQ: XON) began working on a drug for treatment of epidermolysis bullosa: FCX-007. Essentially, FCX-007 is still the same Laviv, that has been subjected to genetic engineering changes. The cell culture technology belongs to Fibrocell, and Intrexon is responsible for the technology for the genetic engineering changes of these cells.

So, Fibrocell put aside the anti-wrinkle medicine and focused all its attention on two orphan drugs and the preclinical development of a medicine for arthritis (chronic joint inflammation). Despite that wrinkles are the most visible external manifestation of aging, older people have more important problems. And these problems involve the extracellular matrix of all organs and tissues, and not just the skin.

Headquarters
Pennsylvania, USA
Year established
1992
Employees
23
Market cap: $18,44 m
Income: -$11,9 m
Revenue: $21,79 m
(02.09.2019)
Biomarker
Matrix metalloproteinases (MMPs)

Number of medications
Two medications overall at the stage of clinical trials:
FCX-007 (Phase III)
FCX-013 (Phase II).

One medication is on preclinical development stage (arthritis)
Diseases the company is focused on
Bullous epidermolysis
Scleroderma
(autoimmune skin disease)
Arthritis
What age-related diseases and conditions the medications can be useful for
Fibrosis, first of all, and aging of the body in general, as well as of skin, connective tissues, also, for example, kidneys (organs which functional structures consist of an extracellular matrix).

Why?
FCX-013 + Veledimex
FCX-007
Money
Leadership
Partners
Why are we interested in these technologies?
Most of the tissues in our body consist not only of cells, but also of the extracellular (intercellular) matrix. And the so-called connective tissues are generally more likely to consist mostly of the matrix, although there are cells too.

The extracellular matrix serves as a mechanical support for the cells and provides their nutrition. It can be imagined as a three-dimensional canvas of structural proteins (mainly collagen, elastin, and a number of others) and filled with liquid. Cells (fibroblasts) are inserted into this canvas, which in turn synthesize extracellular matrix components and various biochemically active molecules.

Collagen production decreases with age: each year there is 1% less collagen produced in the skin of a person older than 20, which explains its thinning. Problems with other components of the matrix also begin to develop.

Matrix metalloproteinases (MMPs) are involved in the disassembly of the extracellular matrix. This is a complex process, but in order to understand its importance, imagine the formation of blood vessels: firstly, a tunnel in the three-dimensional structure of the matrix needs to be made. MMPs play the role of workers punching a hole for such a tunnel. There are 29 different types of metalloproteinases, each has its own number, so in the academic literature they are usually found under names like MMP-1, MMP-8, etc.

Normally, the degradation and synthesis of the matrix are in balance, and the matrix has the optimal properties for each particular tissue: not too hard, not too loose. With age, the balance is disturbed, which is expressed in various diseases, for example, in fibrosis. The latter is a condition in which connective tissue grows forming scars. It has been shown that MMP-1, MMP-8, and MMP-13 can play an antifibrotic role, since an increase in their level decreases liver fibrosis [3, 4, 5].

On the other hand, it has also been shown that excessive production of MMP-1 in smokers causes premature aging of the skin. Therefore, FCX-013 technology, which can be used to regulate the production of metalloproteinases, turn their synthesis on and off, seems to be optimal for combating various fibrosis.

In September 2018, the FDA approved Fast Track status for FCX-013. This therapy is now going through clinical trials Phase I&II (i.e. Phase I combined with Phase II), and volunteers are being called for.

What technology interests us?
We took interest in two-component gene therapy of medium and localised scleroderma (morphea) - an autoimmune skin disease that is expressed in excessive collagen production.


Collagen production occurs in fibroblast cells. MMPs (substances outside cells that also synthesize fibroblasts and secrete them outside) destroy the already created and "hardened", structured collagen. That is, to solve this problem, one could "ask" fibroblasts to either produce less collagen or to produce more MMPs. Fibrocell chose the second option.

A patient with scleroderma experience thickenings that appear on the skin and in the connective tissues of other organs and structures (blood vessels, muscles, and internal organs). Medium and severe forms of scleroderma cause severe pain and restrict movement. Skin lesions can spread to underlying tissues and muscles.

The therapy proposed by Fibrocell involves two medications: FCX-013 and Veledimex. FCX-013 is genetically modified human fibroblasts in which a lentivirus encoding MMP-1 is integrated. FCX-013 is injected under skin at the lesion sites and MMP-1 produced by the fibroblasts disassemble excess collagen.

The key point is that the fibroblasts introduced under the skin do not produce MMP-1 "at will". They are modified so that the production of MMP-1 takes place strictly under control of the RheoSwitch system (RTS®, developed by Rheogene, which merged with Intrexon in 2007). The system is activated by the second drug, a small molecule called veledimex, which the patient additionally takes in the form of tablets.

As soon as matrix metalloproteinases (MMP-1) disassemble all excess collagen, the patient stops taking the pills and the modified cells of the FCX-013 medication stop producing MMP-1.

The combination of FCX-013 and Veledimex drugs is specially designed to improve the condition of the skin of patients with scleroderma, to "absorb" fibrous formations, and to normalise collagen production.


Another interesting technology that Fibrocell is currently working on—FCX-007
FCX-007 is a therapy for bullous epidermolysis, a rare genetic disease caused by impairment of the synthesis of type VII collagen, which is responsible for binding the epidermis (outer, protective layer of the skin) and the dermis (lower layer of the skin that has, for example, blood vessels). Children born with such a disease are called "Butterfly Children," since their skin is like the wings of a butterfly — fragile and thin, and wounds easily appear on it.

FCX-007 is also based on the patient's own fibroblasts, genetically modified to synthesize the needed type of collagen. The doctor introduces the drug locally, so that the cells "mend" the holes where necessary, and therapy does not make systemic changes in the body.

The FCX-007 received the Fast Track FDA status as well, but a little earlier, in 2017. The results of the clinical trials Phase II were satisfactory, and the company plans to start Phase III.

In April 2019, Fibrocell announced a partnership with Castle Creek pharmaceutical company to develop and commercialise FCX-007 gene therapy.

Maintaining the integrity and balance of the intercellular matrix is an important task in the fight against aging. We urge you to pay attention to companies working in this area.


The contract with Castle Creek: Fibrocell will receive up to $135 million, including up to $30 million in advance payments and 30% of gross profit.



John Maslowski, the current President and CEO, joined Fibrocell back in 2005 (it was still called Isolagen then). Made CEO in 2016. Prior to coming to Fibrocell he worked for Pfizer (then known as Wyeth) for four years, of which three years as Research Coordinator and the last year as Quality Assurance Manager. Before joining Wyeth, Mr. Maslowski held positions of GMP compliance auditor at Merck & Co. for one year and Associate Scientist at Teva for also a year. Mr. Maslowski earned a B.S. in Biology from the Ursinus College and an M.S. in Biology from Villanova University in 1999.

Anna Malyala is the Vice President of Research and Development (since 2018). She has been with Fibrocell since 2015. Prior to that, she held executive positions at Intrexon for four years, where she focused on new product planning, disease strategy, and early drug development. In 2008-2009, Anna Malyala was a Research Manager in the Healthcare Practice at Gerson Lehrman Group, where she managed and executed primary research deliverables for investment firm clients. Anna Malyala earned a Ph.D. in Neuroscience from the Oregon Health & Science University School of Medicine.


Castle Creek Pharmaceuticals is a privately owned company specialising in the treatment of epidermolysis bullosa. The company was founded in 2015 by Michael Derby, an entrepreneur with twenty years of experience in the pharmaceutical industry and the wider life sciences sector. He worked at Merck, EGS Healthcare Capital Partners, and Revogenex. The total funding amount was $ 119.8 million. Two drugs are currently under development, one jointly with Fibrocell: FCX-007. There are no FDA approved drugs. The current CEO, Greg Wujek, is also part of the industry consultancy at Third Bridge, Reuters, Gerson Lehrman Group. Strategies he developed were implemented by Forest, Andrx, Savient, and Zimmer Biologics Paragon.

Intrexon Corporation (NASDAQ: XON) is a public company, founded in 1998. It is one of the leading companies in synthetic biology, which is focused on human and animal health, energy and chemicals, and the environment. In April 2019, Intrexon formed two divisions - Intrexon Health (medicine) and Intrexon Bioengineering (application of biotechnologies in agriculture and livestock, food and energy industries). Intrexon Health's CEO is Randal J. Kirk.

In 1999, Randal Kirk set up Third Security, an investment firm in the life sciences field (he is the current CEO of the company). From 2000 to 2002, Kirk was a member of the board of directors at Scios, which only drug, Natrecor, was approved in 2001. Giant Johnson & Johnson acquired Scios in 2003 for $2.4 billion. Analysts predicted that such an acquisition would increase drug sales, as Joshnson & Johnson could provide better promotion.

Kirk also became a major shareholder and the chairman of Clinical Data, Inc. pharmaceutical company. In 2011, after its drug Vilazodone had been approved, Forest Laboratories bought Clinical Data for $ 1.2 billion.

Forbius

Formerly known as AvidBiologics, Formation Biologics.

A company that develops drugs for cancer and fibrosis, targeted at the molecular pathways TGF-β and EGFR (the main culprits of oncological diseases and fibrosis: the fact which there is enough evidence for).


TGF-β is a transforming growth factor beta, a multifunctional signalling molecule secreted by white blood cells. One of its key functions is the regulation of inflammatory processes. TGF-β also plays an important role in stem cell differentiation. There is also a number of other functions, as is often the case in biology.
EGFR is a transmembrane receptor that can respond to epidermal growth factor (EGF), binding it. EGF is a protein that stimulates the growth of cells in many tissues as well as cell differentiation.
Headquarters
Austin (Texas, USA) and Montreal (Canada)
Year established
2011
Employees
11–20
Biomarker
TGF-β (трансформирующий фактор роста бета)
Number of medications
We took interest in just one, but in total the company has four drugs at the stage of clinical trials.

Diseases the company is focused on
Solid cancers, fibrosis
What age-related diseases and conditions the medications can be useful for
Cancer, osteoarthritis, myocardial infarction, fibrosis
Myocardial infarction
Osteoarthritis
Hypothalamus
AVID200
Leadership
Why are we interested in this technology? TGF-β and myocardial infarction
There are several diseases, beside cancer, the development of which TGF-β plays an important role in. For example, its level rises with myocardial infarction, which exacerbates the development of the disease.


Myocardial infarction - damage to the heart muscle due to blockage of one of the arteries of the heart. Insufficient blood supply leads to the immediate death of cardiomyocytes, and then fibrosis and formation of scar tissue, which further leads to myocardial dysfunction and heart failure.


Concerning heart fibrosis, TGF-β is a "Jack of all trades": it can trigger apoptosis in cardiomyocytes and control the conversion of heart fibroblasts to myofibroblasts, which produce extracellular matrix components and repair damaged tissue. But if the process gets out of control, myofibroblasts begin to secrete too many components of the matrix, which replaces muscle tissue. As a result, fibrosis develops; part of the heart tissue is replaced by a connective one that has no function there.


Why are we interested in this technology? TGF-β and osteoarthritis
Another age-dependent disease in which TGF-β is involved is osteoarthritis. It was shown in an experiment with osteoarthritis in a mouse model that an increased level of TGF-β1 in osteoblasts causes the development of this disease, and inhibition of TGF-β1 slows it down.


TGF-β plays an important role in the functioning of joints. This super-family is involved in a large number of cellular processes in the cartilage tissue, in the differentiation of chondrocytes, and the restoration of cartilage. However, other studies indicate that TGF-β may contribute to hypertrophy. This can be explained, at least in part, by changes in TGF-β signalling pathways in aging chondrocytes.



Why are we interested in this technology? TGF-β and the hypothalamus
In the hypothalamus, the excess of TGF-β is observed not only in those who suffer from obesity, but also in the elderly. Moreover, obesity and old age are serious risk factors for developing diabetes. It has been shown that excess TGF-β in the brain causes hypoglycemia and glucose intolerance, regardless of body weight.

Other experiments have shown that the excess TGF-β in the hypothalamus causes inflammation. How? First, in response to stress (which an excess of TGF-β is), special RNAs are produced, which, in turn, leads to atypical activation of NF-κB in the hypothalamus. Thus, inflammation occurs due to the excess TGF-β and it is associated with obesity and aging.

Nf-kB is another multifunctional regulatory molecule, the so-called transcription factor. It controls the production of products (proteins and RNA) of the genes for the immune response, apoptosis, and the cell cycle. In turn, NF-kB is controlled by many stimuli, including TGF-β. If this regulation goes out of control, inflammation, autoimmune diseases, cancer, and viral infections develop.

Diabetes, myocardial infarction, and osteoarthritis: all these age-related diseases are closely associated with the excess TGF-β, and it would be great to be able to inhibit it locally (and controllably).


What technology interests us?
AVID200 medication is a powerful inhibitor (substance that suppresses activity) of TGF-β isoforms 1 and 3, the main driving forces for the development of fibrosis in myelofibrosis and other fibrotic diseases.


Myelofibrosis is a rare form of blood cancer characterised by progressive bone marrow fibrosis, in which the production of red blood cells is significantly reduced. The frequency of the disease varies in different populations: 0.3–1.5 cases per 100,000 people per year. However, about 30,000 people suffer from myelofibrosis in the United States alone, and today there is no treatment aimed at reducing bone marrow fibrosis in myelofibrosis.


The old generation TGF-β inhibitors were nonspecific, that is, they also inhibited the TGF-β isoform 2 responsible for the normal cardiac and hematopoietic function, and that caused serious side effects in the cardiovascular system. AVID200 is expected to be a more effective and safer drug.


On April 24, 2019, the first patient of those suffering from myelofibrosis was administered the first dose of AVID200 (clinical trial Phase 1b). This study is sponsored by the Icahn School of Medicine at Mount Sinai and the Myeloproliferative Neoplasm Research Consortium (MPN-RC), and also the NIH issued a grant [6, 7].


The CEO of the company is Ilya Tikhomirov. He got bachelor's and PhD degrees from the University of Toronto, and a master's degree in business administration from the Rotman School of Business. Before joining Forbius, Ilya held increasingly important positions at YM BioSciences Inc. (YM), a public cancer drug company acquired by Gilead Sciences as a result of a $ 500 million deal. Forbius split from YM before the acquisition.


Maureen O'Connor-McCourt is the Chief Scientific Officer at Forbius. She has published over 100 peer-reviewed manuscripts, including over 50 publications related to TGF-β. She holds numerous patents. Prior to joining Forbius, Maureen has been Principal Research Officer and Section Leader at the Canadian National Research Council (NRC). She received her Ph.D. in Biochemistry from the University of Alberta and completed post-doctoral training at the Dr Michael Sporn and Dr Anita Roberts laboratory, where TGF- β proteins and their relation to carcinogenesis was first discovered.


Sanofi Genzyme

The double name, Sanofi Genzyme, is not accidental. In February 2011, the French pharmaceutical giant Sanofi-Aventis bought Genzyme (along with the technology we are interested in) for $ 20.1 billion. A little later, in May 2011, the giant simplified its name to just Sanofi. And now there is a subsidiary Sanofi Genzyme in the Sanofi family.

Jumping ahead, we would like to add that Sanofi took part in the fate of another company in our list. Sanofi had bought not that company itself, though, but a whole set of drugs from it: Sanofi agreed to incur development costs, as the inventor company could not independently complete the first phase of clinical trials, and to share the profits. We are going to tell the whole story later.

Genzyme, at the time it was bought by Sanofi-Aventis, was the third largest biotechnology company in the world: it employed more than 11,000 people, and its net profit in 2010 was $ 400 million (with the revenue of $ 4 billion). By this time, enzyme therapy had brought the company about 40% of its revenue - the portfolio managed by the Personalized Genetic Health division was the largest of the five operating units. The company sold the Genzyme Genetics division for $ 925 million to LabCorp the same year. The director of LabCorp said then that it was one of the leading genetics and oncology laboratories in the United States.
The part of the history of Genzyme we are interested in begins with the medication called Fresolimumab (aka GC1008): a monoclonal antibody that binds and inhibits all TGF-β isoforms. This human antibody and immunomodulator is intended for the treatment of (1) idiopathic pulmonary fibrosis, (2) focal segmental glomerulosclerosis, (3) kidney cancer, and (4) skin (melanoma).

The drug was discovered by scientists from the Cambridge Antibody Technology (CAT) laboratory and was one of two candidates for the treatment of scleroderma (the one we wrote about above). The CAT team selected metelimumab (CAT-192) and fresolimumab to be developed together with Genzyme. In 2005, after unsuccessful clinical trials, CAT and Genzyme decided to abandon metelimumab in favour of fresolimumab.

In February 2011, Genzyme became a part of Sanofi Genzyme (although the process of transfer of powers began in November 2010, as shown in the figure on the right), and in June the same year fresolimumab was tested on patients suffering from idiopathic pulmonary fibrosis, focal segmental glomerulosclerosis, or cancer. A list of all clinical trials of the drug, registered in the USA, can be found here.

Sanofi Genzyme now has an impressive list of drugs (about 50) at the clinical trials stage. Most of them are monoclonal antibodies.



The history of Genzyme:
What company bought what company and when (click on the image to enlarge)
Parent
Sanofi (France)
Year of the merger with Sanofi
2011
Employees
12,000 at the time of the merger with Sanofi
Sales for the fourth quarter of 2018
7,228 m
Biomarker
TGF-β (transforming growth factor beta)
Number of medications
More than 50 in development and clinical trials stages and 25 have already been approved by the FDA
Diseases the company is focused on
Idiopathic pulmonary fibrosis, focal segmental glomerulosclerosis, kidney cancer, and melanoma
Для каких возрастных заболеваний и состояний может пригодиться
Рак, фиброз, остеоартрит
SAR339375 (RG-012)
How the merger with Sanofi changed Genzyme
Partners
What technology interests us and why?
To tell the truth, at first, we were interested in fresolimumab. But its capacity to inhibit all isoforms of TGF-β can interfere with therapy (as is described above), so, to inhibit TGF-β, we are considering the product that is being tested by the Forbius, the company that precedes Sanofi Genzyme in our list.


However, having carefully looked at Sanofi Genzyme's portfolio, we found another interesting drug - SAR339375 (RG-012), intended for the treatment of Alport syndrome, which is an siRNA-21 oligonucleotide (antimiRNA-21). In the future this technology will probably also help in the treatment of fibrosis and cancer. And that is the second known case when Sanofi took part in the fate of another company in our list and in the development of a medication that is of interest to us.

Sanofi Genzyme is a huge corporation. Let's take a closer a look at this second case, of the company Regulus Therapeutics, which originally developed RG-012, in another text below.
In February 2011, Genzyme and Sanofi agreed on a deal worth about $ 20.1 billion (yes, we have already mentioned this figure, but we do it again: it was an enormous deal). As a result, Sanofi gained access to the Genzyme rare disease business, and in return Genzyme could expect help in promoting drugs and competing with generics.

Everyone seems to have benefited from the deal. Sanofi Genzyme continues to develop drugs for the treatment of rare diseases, announcing at the end of 2018 that it would now also focus on blood cancer and rare hematological diseases. Relationships with the FDA could be considered friendly - in the sense that the FDA is supportive of development of drugs for the treatment of rare diseases. Information on how clinical trials are conducted and which drugs have been approved by the FDA can be found on the company's official website.

The acquisition of Genzyme has become a real driving force for Sanofi's transformation from an old pharmaceutical giant based on chemistry and small molecules into a modern biotechnological giant.

Regeneron, an American biotechnology company. Market capitalisation - $ 31 billion, sales - $ 7 billion, revenue - $ 2 billion. Dupixent Medication, an IL-4 and IL-13 inhibitor developed jointly with Genzyme, was approved this year for treating atopic dermatitis and last year for treating asthma.

Sangamo Therapeutics, an American biotechnology company. Market capitalisation - $ 31 billion, sales - $ 76 million, revenue is negative, minus $ 103 million. It uses cell and gene therapy to treat haemophilia and other genetic diseases.

Roche, a Swiss pharmaceutical giant, with a market capitalisation of 233 billion Swiss francs.

Revolution Medicines, a private company with total funding of $ 226 million.

BioNtech, a private biopharmaceutical company, with total funding of $ 686 million.

Immunext, a private company specialising in the development of cancer immunotherapy.

Denali Therapeutics, an American biotechnology company with a market capitalisation of $ 1.79 billion, negative revenue, minus $ 55 million, and sales of $ 135 million.

Lead Pharma, a private biopharmaceutical company focused on developing drugs for the treatment of autoimmune diseases and cancer (small molecules).

Principia Biopharma, an American biopharmaceutical company specialising in the development of drugs for the treatment of immunological and oncological diseases. Market capitalisation - $ 938 million, revenue is negative, $ 1.7 million, sales - $ 79 million.

Regulus Therapeutics

Биофармацевтическая компания, занимается разработкой олигонуклеотидов, направленных на связывание микроРНК.
MicroRNAs are small RNA molecules, usually 20–25 nucleotides in length, that do not encode proteins but regulate gene expression (that is, the process of protein production).

In academic literature, the names of these molecules look like the prefix miR followed by a hyphen followed by a number, e.g. 'miR-21'. A number simply indicates when a given molecule was discovered, that is, miR-752 was discovered later than miR-751 and earlier than miR-753. 1800 microRNAs had been discovered overall by 2014.
The goal of microRNA-based therapy is to suppress specific microRNAs (or miRNAs). Experiments on animal models have shown that this therapy works for cardiovascular disease, cancer, and hepatitis C.
An oligonucleotide is a short fragment of RNA or DNA obtained either by synthesis or by cleavage of a fragment from a large chain (oligo is the Greek for "a little"). In miRNA-based therapy, such short fragments are needed that would specifically (complementarily) bind to miRNA, thereby blocking its activity.

Headquarters
Carlsbad, California, USA.

Parent organizations: Alnylam Pharmaceuticals, Ionis Pharmaceuticals
Year established
2007
Number of employees
21
Finances
Market cap: $12,653млн
Income: -$27 m
Revenue ttm: $6,8 m
(02.09.2019)
Biomarker
miRNA-21
Number of medications
Two medications overall, we are interested in one of them, RG-012
Disease the company is focused on
Alport syndrome
What age-related diseases and conditions the medication might be useful for
Fibrosis, cancer
Why?
RG-012
Biobucks
Who is who
Why this technology interests us?
More and more data indicate that miR-21 can play an important role in the development of fibrosis, contributing to the division of fibroblasts and increasing the production of extracellular matrix components [8, 9]. In fibrotic diseases, expression of miR-21 is elevated and it can be used as a potential diagnostic and prognostic marker, and even as a therapeutic target.
What does this technology interest us?
We are interested in the therapy of Alport syndrome—RG-012, an oligonucleotide that binds and inhibits miRNA-21.

Alport syndrome is a condition caused by mutations or defects in the type IV collagen genes, which are necessary to maintain the integrity of the kidneys' structure. Gene defects cause scarring of the glomerular basement membrane, part of a kidney necessary for filtering the blood. Such scarring leads to progressive loss of kidney function and ultimately the patient develops the need of frequent dialysis or organ transplant procedures.

In the process of fibrosis' development in Alport syndrome, miRNA-21 (miR-21) suppresses proteins in the PPARα signalling pathway, which can perform a protective function in the kidneys.

RG-012, the molecule complementary to miR-21, binds the latter and interferes with its functioning. By blocking miR-21 the preparation cancels the inhibition of the PPARα pathway and thus can reduce the symptoms of Alport syndrome.

Last year, the company had to suspend clinical trials (Phase I) for financial reasons, but in November 2018, the aforementioned Sanofi company (the huge one that we decided not to talk about until now) incurred the development costs [10, 11].

Now, all Regulus programs based on miR-21, including RG-012, are owned by Sanofi. As of March 31, 2019, the transfer of powers has been completed. Overall, Regulus received $ 6.8 million from Sanofi, which was credited as revenue as of the end of the first quarter 2019. Regulus also has the right to receive up to $ 40 million from Sanofi upon reaching significant clinical results (clinical milestone payment).
What is it and what role do they play in the development of the company?
Biobucks (biodollars) is a slang word in the world of biotechnology and clinical research, used sometimes instead of the official term, biotech milestone payment. This is a payment that a larger partner company agrees to pay to its lesser partner if the latter successfully completes certain stages of research. Payments, their amounts and agreed schedule may differ. Essentially, effectiveness of the drug must be proved. For example, only 9.6% of drugs receive FDA approval upon successful completion of clinical trials Phase I (safety tests with healthy volunteers). Read more about the difference between real dollars and biobucks here.


By the way, Sanofi invested $10 million in Regulus back in 2010, to fight fibrosis. Thus, Sanofi joined Alnylam Pharmaceuticals and Isis Pharmaceuticals as a Regulus investor. Then it was an equivalent to 10% of the Regulus property as if belonging to Sanofi and the rest to Alnylam and Isis equally.

The collaboration of Regulus and Sanofi was then valued in excess of $ 750 million. It covered the discovery, development, and commercialisation of miRNA therapy, including Regulus's leading fibrosis program targeting miRNA-21.

Sanofi was not the first Big Pharma company to invest in miRNA. The first was GlaxoSmithKline: for a prepayment of $ 20 million, the company obtained the right to work with Regulus on the discovery, development, and implementation of miRNA therapy for rheumatoid arthritis and inflammatory bowel diseases. The total value of the deal amounted to about $ 600 million.


Joseph P. "Jay" Hagan joined Regulus in January 2016 as Chief Operating Officer, Principal Financial Officer and Principal Accounting Officer. He was appointed President and CEO in May 2017.

In the course of his career, Joseph Hagan was Executive Vice President and Chief Business Officer at Orexigen Therapeutic (specialises in obesity treatments), Managing Director at Amgen Ventures and head of corporate development for Amgen Inc. (a pharmaceutical giant of 19,000 employees and a market capitalisation of about $ 125 billion). He has led numerous strategic and financial transactions, including Amgen's acquisition of Immunex and Tularik, the spinout of Relyspa, and handing of Novantrone medication to Serono company. Before joining Amgen, Joseph Hagan had spent five years in bioengineering laboratories at Genzyme and Advanced Tissue Sciences.

He is currently a member of the board of directors of Zosano Pharma (NASDAQ: ZSAN). He received M.B.A from Northeastern University of Boston and B.S. in physiology and neuroscience from the University of California, San Diego.

Fibrogen

The company specializes in cell and gene therapy for skin and connective tissue diseases.

The company has developed a unique technology based on patients' own fibroblasts: cells are taken from the patient's skin, subjected to genetic engineering changes, and administered back to the same patient. This way gene therapy becomes 'localised', which increases efficiency and reduces side effects.

The new drug should prove effective and safe in the course of the Phase III of clinical trials, which is conducted with a large group of people. Also, in order to be approved by the FDA, the new drug must be better (more effective, safer, more convenient) of all existing drugs intended for the treatment of the same diseases. For roxadustat, epogen was such a competitor.
It was officially stated that there is no clinically significant risk difference between the drugs: "We believe there is no clinically meaningful difference in risk". This discrepancy made investors doubt the safety of the drug. Most likely, the risks are about the same. For some groups of patients roxadustat was slightly more effective than epogen, so analysts predict that the FDA is likely to approve roxadustat. Still, the investors are disappointed: since Roxadustat turned out to be only marginally better than epogen, a drug with thirty years of experience, sales of a new drug might be slow and would not bring a lot of money.
In 2017, another drug, pamrevlumab, caused quite a stir, successfully passing the second phase of clinical trials. Fibrogen shares then rose 1.5 times.

Generally, the mere fact that a company's shares are rising or falling does not mean anything. It rather reflects the degree to which society hopes for the success of the drug. Pamrevlumab is indeed a promising drug, and we are going to tell more about it.
Headquarters
San Francisco (California, USA)

Additional offices: Beijing and Shanghai (China)
Year established
1993
Number of employees
461
Finances
Market cap: $3,984 b
Income: $49.00 m
Revenue ttm: $352,50 m
(02.09.2019)
Biomarker
CTGF (connective tissue growth factor)
Number of medications
We are interested in Pamrevlumab, one of the three company's medications
Disease the company is focused on
Idiopathic pulmonary fibrosis (IPF), pancreatic cancer, Duchenne muscular dystrophy
What age-related diseases and conditions the medication can be useful for
IPF itself is an age-related disease. It is also possible that the drug will be helpful in Alzheimer's disease.
IPF
Pamrevlumab
Why?
Who is who
The drug, thanks to which the company's shares jumped in 2017, is pamrevlumab. It is intended for the treatment of idiopathic pulmonary fibrosis (IPF), that is, pulmonary fibrosis of unknown origin.

IPF is a chronic, progressive lung disease in which normal tissues are gradually replaced by scar tissue and so the lungs gradually lose their ability to effectively transfer oxygen to blood.

The disease usually affects older people of ages between 50 and 70. The prevalence rate is 12 to 20 cases per 100,000 people, and about 40,000 cases are recorded annually in the United States alone. Life expectancy of most patients after the diagnosis of IPF is 3-5 years but can vary between several months and tens of years.

Risk factors for developing IPF include old age (most patients are older than 50), smoking, acid reflux (about 75% of patients with IPF suffer from it), and a genetic predisposition.

IPF begins with a continuous inflammation in the lungs. For example, in the case of acid reflux, the patient constantly inhales tiny droplets of acid that damage the alveolar epithelial cells. Constant inflammation develops, cytokines and growth factors are activated, which leads to fibrosis (see the figure in the part "Why").

What technology interests us?
Pamrevlumab is a monoclonal antibody that inhibits the activity of connective tissue growth factor (CTGF). This growth factor is the key mediator of the development of fibrosis (as its name indirectly indicates).


CTGF, a connective tissue growth factor, plays an important role in many biological processes, including cell adhesion, migration, proliferation (cell growth), vascular growth, and skeletal development. It is also involved in development of fibrotic diseases and several forms of cancer.


In Phases I and II of clinical trials, in which more than 450 patients participated, pamrevlumab was well tolerated by the patients in a wide range of doses without any dose-limiting toxic effects [12, 13].

It was shown earlier in experimental model of fibrosis that pamrevlumab can reverse the development of fibrosis. It happened in some patients in the second phase of clinical trials, i.e. the lung volume was restored. The report on this clinical study in 2017 was so promising that it caused an incredible increase in the value of the company's shares (as we mentioned above).

In April 2019, the FDA approved Fast Track status for the treatment of Duchenne muscular dystrophy. This genetic disease, mainly affecting boys, is expressed in the progressive destruction of muscle fibers. Most patients lose the ability to walk between the ages of 6 and 13.

Pamrevlumab has also received a fast track FDA status and orphan drug status for the treatment of IPF and pancreatic cancer.

To give you a more complete view of Fibrogen, we should also mention the biosynthetic cornea it is currently developing. This 'spare part' is based on the recombinant collagen FG-5200.

Ten patients with advanced keratoconus (thinning of the cornea) or severe corneal scarring were transplanted such a cornea, after which they were being monitored for four years. The results were good: patients' vision improved and the sensitivity of the cornea to touch restored.

The preclinical safety trials required before conducting clinical trials in China are currently underway.
Почему эта технология нам интересна?
CTGF plays a key role in other diseases as well. Pancreatic cancer, liver fibrosis, and diabetic kidney disease are among them. The anti-CTGF antibody, pamrevlumab, seems to be a promising drug for their treatment.

CTGF is closely associated with inflammation, e.g. it is activated by TGF-beta.

The expression of CTGF in the brain of patients with Alzheimer's disease correlates with the progression of clinical dementia and amyloid load.

The level of CTGF changes with age, but the reasons for this are not yet fully understood. The topic is discussed in detail in this review, but here we present only a picture.

What do antibodies against fibrosis and biosynthetic corneas based on recombinant collagen have in common? Extracellular matrix. And Fibrogen is one of the companies dealing with it.
Sad news came on August 27, 2019 - Thomas Neff, the founder and CEO of the company, died suddenly. And that happened when his brainchild Roxadustat is entering the final stretch and is expected to be presented to the FDA in the third quarter [НЕПОНЯТНО, КАКОГО ГОДА! – Н.]. The drug was approved last year in China, is under consideration in Japan, and is approaching approval in Europe.

The new CEO is James A. Schoeneck, a member of the board of directors since April 2010. James Schoeneck has a lot of managerial experience: he was the CEO of Depomed Inc., the CEO of BrainCells Inc. (no longer exists), the CEO of ActivX BioSciences, the President and CEO of Prometheus Laboratories Inc., the Vice President and General Manager, Immunology, at Centocor Inc. (now Janssen Biotech, Inc.). His group launched Remicade®, which has become one of the world's largest pharmaceutical brands. At the beginning of his career, he spent 13 years at the pharmaceutical company Rhone-Poulenc Rorer Inc. (now Sanofi), holding various positions of increasing responsibility in sales and marketing. Jame Shenek holds a B.S. in Education from Jacksonville State University.

Foresee Pharmaceuticals Co., Ltd.

FP has two core technologies: Drug Delivery Technology and Rational Drug Design. The company's main drugs are FP-001, which is used to treat prostate cancer, and FP-025, which is designed to treat asthma and COPD.
Asthma is a chronic inflammatory disease of the respiratory tract. External irritants cause airways contraction, swelling, and mucus secretion. As a result, the airways narrow making breathing difficult.
Chronic obstructive pulmonary disease (COPD) is a lung lesion that develops as a response to prolonged exposure to irritating agents (tobacco smoke, air pollution) and the associated chronic inflammation.
Headquarters
Taipei City, Taiwan и Newark, Delaware, USA
Year established
2011
Number of employees
11–20
Market cap
$228 m
(02.09.2019)
Biomarker
Matrix metalloproteinase (MMP)
Number of medications
Seven drugs overall at various stages from development to research, we are interested in just one
Disease the company is focused on
Asthma and chronic obstructive pulmonary disease (COPD)
What age-related diseases and conditions the medications can be useful for
COPD and arterial stiffening
FP-025
Why?
Partners
Who is who
What technology interests us?

We liked the FP-025 medication, an inhibitor of metalloproteinase 12 (MMP-12).

The drug has successfully passed the first phase of clinical trials (NCT03304964) and is now in the second phase (NCT03858686).

FP-025 suppresses the operation of MMP-12. The latter is a key enzyme that directs inflammatory cells and plays an important role in the development of asthma and COPD.


MMP-12 is an enzyme that promotes the cleavage of peptide bonds within the peptide chain. It is effective primarily against elastin (an extracellular matrix elastic protein), for which reason it is also called elastase. But it also breaks down other extracellular matrix proteins, including type IV collagen, fibronectin, laminin, and others.

Why does this technology interest us?
Around 300 million people in the world are affected by asthma, according to the Global Initiative for Bronchial Asthma (GINA). The situation in the developed countries is only getting worse.

COPD is now one of the leading causes of death: 3.2 million deaths in 2015, accounting for 5% of deaths that year. In 2016, there were 250 million patients with COPD in the world (data from Global Burden of Disease, GBD, death data not available). And according to the World Health Organization data, by 2030 COPD will become the third leading cause of death, if current trends continue.

This is already enough to make FP-025 interesting in terms of prolonging life. But an MMP-12 inhibitor may not only be useful in treating asthma. Why is MMP-12 bad and why should it be inhibited?

MMP-12 is a powerful elastase, i.e. theoretically it can greatly reduce the elasticity of organs and structures. It was shown in experiments on mice that it plays a key role in acute and chronic increase in arterial stiffening, most likely due to the reorganisation of the extracellular matrix of the arterial walls.

In humans, the level of MMP-12 correlates with stiffening markers for smooth muscle cells in arteries. But an increase in arterial stiffening is a sign of aging and a risk factor for cardiovascular disease.

In rats and mice, MMP-12 rises in the brain after a stroke. It was also shown that in rats MMP-12 causes damage to the blood-brain barrier. The authors of this work claim that suppression of MMP-12 may be a promising therapeutic target for cerebral ischemia, a common diagnosis of the elderly.
Pierre Fabre Medicament Production (PFMP), located in Pau (Pyrénées-Atlantiques, France), is a strategic partner and contract manufacturer of pre-filled syringe FP-001. PFMP was the first manufacturer in France approved by the FDA in 1993.

ScinoPharm (Taiwan), a strategic partner of Foresee, is responsible for the development and commercial production of the drug used in FP-001.
Benjamin M. Chien is the founder and the CEO of Foresee Pharmaceuticals.

The story goes like this: Benjamin first founded QPS (Quest Pharmaceutical Services) in 1995. The company was created to provide high-quality bioanalytical contractual services using LC MS/MS method (liquid chromatography and tandem mass spectrometry) methods. Since then, QPS has grown from a modest small molecule bioanalysis firm that employs three people to a large company with more than 1,150 employees and branch offices in the United States, Europe, India, and Asia. Meanwhile Foresee company was founded as a QPS research unit in 2011.

Ben earned a PhD in analytical chemistry (mass spectrometry) from the University of Michigan at Ann Arbor under the supervision of Professor David M. Labman.
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