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.

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.

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.

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.

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.

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).

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.

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.

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.

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).

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.

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").

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.

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.

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.

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.