Dual Antibody Treatment Knocks Down HIV Viral Loads in HIV-Infected Patients


According to two early-stage clinical trials reported in the journals Nature and Nature Medicine, a combination of two different antibodies against the Human Immunodeficiency Virus (HIV) have successfully diminished the virus levels in patients not taking anti-HIV medications.  Infusions of these antibodies kept virus levels low in the blood of a percentage of these patients for two-three months, after which, blood quantities of HIV in these patients rebounded to their previous levels.

HIV is a member of a special class of viruses called “retroviruses.”  Retroviruses receive their name from their ability to take an RNA copy of their genome and make a DNA copy of it.  This process, called “reverse transcription,” is backwards from the way cells normally do things.  In cells, genetic information is stored by DNA (deoxyribonucleic acid), and enzymes called RNA polymerases make an RNA copy of stretches of DNA.  The process by which RNA copies are made from DNA is called “transcription.”  In retroviruses, an enzyme called “reverse transcriptase” makes a double-stranded DNA copy of a single-stranded RNA genome.  This transcriptional process reverses the direction of transcription; hence the name “retroviruses.”

Below is a picture of a HIV particle.  The virus is surrounded by an envelope that is derived from the membranes of the host cell from which it budded.  Inserted into those membranes are viral proteins that are decorated by sugars.  These sugar-coated proteins are called “glycoproteins.”  The HIV surface glycoproteins are called gp120, which means that the glycoprotein weighs 120 kilodaltons (a Dalton is the weight of a hydrogen atom and a kilodalton is the weight of 1,000 hydrogen atoms), and this viral glycoprotein is anchored to the viral membrane by means of another protein called gp41.

HIV capsid

 

These two glycoproteins are the first thing that the acquired immune response responds to.  Unfortunately, the viral reverse transcriptase is extremely error-prone and makes lots of mistakes as it copies its viral RNA genome into DNA copies.  This means that when HIV infects cells, it produces progeny virus particles that vary tremendously.  When these variant viruses particles are put under intense selective pressure, as in the case when the immune system makes antibodies against it or when the viruses is brushed back by means of highly active antiretroviral therapy (HAART), the variant viruses that survive the best (and show the highest levels of resistance to the treatment of immune system-based attack) will emerge as the dominant strain of virus in the infected person and as the treatment strategies change, so will the virus in adaptation to the latest attempts to eradicate it.  It is an insidiously efficient mode of evading antiretroviral drugs and the immune system.  HIV also infects and destroys T4 lymphocytes (T-helper lymphocytes), which are essential for activating B lymphocytes.  Thus, HIV not only evades the immune response, but it permanently hamstrings it as well.

When a patient makes antibodies against the HIV surface glycoproteins, the virus simply changes the amino acid sequence of the protein and those neutralizing antibodies no longer prevent the virus from infecting cells.  Therefore, scientists have worked very hard to make custom antibodies that neutralize the virus in such a way that would make it difficult for the virus to adapt.

Michel Nussenzweig, an immunologist at the Rockefeller University who led these studies and his colleagues, have made custom (“monoclonal” antibodies against specific pieces of gp120.  Specifically, their custom antibodies target the base of the so-called “V3 loop” and the surrounding sugars.  Past work shows these antibodies (3BNC117 and 10-1074) that target this one spot reduces virus levels in human patients infected with HIV (Caskey, M. and others, Nature 522, 487–491 (2015); Lynch, R. M. and others, Sci. Transl. Med. 7, 319ra206 (2015); and Caskey, M. and others, Nat. Med. 23, 185–191 (2017).  Infusions of the antibody called 3BNC117 reduced virus levels of about 28 days in HIV-infected patients and 10-1074 reduced virus levels for one week in HIV-infected patients after which antibody-resistant viruses began to emerge.  Nussenzweig and his group then had the novel idea of treatment patients with both antibodies and not just one of them.  This way, the virus would have more hurdles to jump in order to adapt to this treatment.

In one of the clinical trials, 15 HIV-infected patients who had stopped taking all antiretroviral medications received three infusions of both monoclonal antibodies.  Of these 15 patients, nine of them showed a significant reduction in viral load for 15 – 30 weeks, after which, virus levels in the blood rebounded.

In the second clinical trial, seven HIV-infected patients who had never taken antiretroviral drugs were given infusions of the two monoclonal antibodies.  Initially, patients received infusions of 30 mg kg−1 of each of the antibodies and these infusions were very well tolerated.  In those four patients whose HIV viral profile showed sensitivity to the dual antibody treatment in laboratory tests, this therapy reduced HIV-1 viral load by two factors of ten.  This viral load reduction continued for three months following the first of up to three infusions. Additionally, and this is potentially the most exciting part of this study, none of these individuals developed resistance to both antibodies.  According to The Scientist, the viral loads of these patients rebounded; it is possible that these patients stopped receiving the antibody treatments (I only have access to the abstract of the Nature Medicine article).  However, the fact that the sensitive viruses stayed susceptible to the dual antibody treatment is quite encouraging.

Antibody treatments are diabolically expensive because making hybridoma cell lines that create the monoclonal antibodies is ridiculously labor- and resource-intensive.  For this reason, Nussenzweig said, “Ultimately, this may not be good for everybody, and it’s expensive.”

When HIV-infected patients are placed on HAART, they must take those drugs daily, for the rest of their lives.  These drugs have some potentially serious side effects, but they do tend to reduce progression of HIC infection to full-blown AIDS and reduce HIV-induced mortality (Kitahata, MM and others (2009), New England Journal of Medicine. 360 (18): 1815–1826; Lundgren, JD and others (2015), New England Journal of Medicine. 373 (9): 795–807; Danel, Christine and others (2015), The New England Journal of Medicine. 373 (9): 808–822).  Neutralizing antibodies against the virus may provide longer-lasting treatments, but, to date, HIV quickly adapts to experimental antibody treatments (for example, see Trkola, A. and others, Nature Medicine 11, 615–622 (2005).

 

“Antibodies can be used as a safe, new treatment to allow people to go ‘off’ of drugs for several months,” Nancy Haigwood, an AIDS researcher at Oregon Health & Science University who was not part of these studies.

Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, said that this work represents an “early step” toward antibody-based HIV interventions.

Both these studies are small, and only included a few patients.  What we can glean from there, therefore, is limited.  However, there are some definite bright spots from them.  First of all, the dual antibody treatment was well tolerated in these patients.  This suggests that antibody treatments might be rather safe.  Again, larger studies are needed, but this is a potential bright spot of this study.  Secondly, the dual antibody treatment did significantly reduce viral loads for some time in a percentage of both groups of patients.  Thus, if the right antibody combination is found, it could potentially do some real damage to HIV levels in patients with susceptible viral populations.  Third, the antibody-based treatment strategy might actually work in some cases.

The caveats are many.  One is the cost.  Such mass treatments of HIV patients around the world will prove horribly expensive and third-world countries with the largest HIV load will simply not be able to sustain such costs.  Secondly, how long can such treatments give relief to patients when the virus simply adapts after a few weeks or months.  Therefore, feasibility of antibody-based treatments are a second problem.  Once potential use for antibody-based treatments that occurs to me are for those patients whose toxicity from HAART is just too onerous and the antibody-based treatments can give them a drug holiday to heal.  Such patients would need to be pre-screened to ensure that their virus population is susceptible to the antibody treatment before starting it.  Such HAART holidays may also cause a shift in their viral population to strains that are more susceptible to the HAART regimen they are taking.  Therefore, such drug holidays/dual antibody treatments might (a big might) have knock-off benefits.

In any case, this early, preliminary data is hopeful, but it is just the beginning if antibody-based treatments are to make it to the clinic.

 

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Stem Cells from Baby Teeth Regenerate Dental Pulp after Implantation into Injured Teeth


Going to the dentist is usually not anyone’s idea of fun.  In particular, root canals are no fun.  However, if you have an abscessed tooth that hurts like the dickens, then a root canal may be your best bet for resuming normalcy.

In younger patients, the innermost part of the tooth, the pulp, may die off for a variety of reasons.  This phenomenon, known as “pulp necrosis” arrests root development and may result in tooth loss.  Injury to the pulp as a result of trauma, inflammation, tooth decay, or infection can result in the irreversible loss of teeth.

Tooth-Anatomy

Regenerating dental pulp has proven to be a bear.  Getting the mass of blood vessels and nerves to regrow is not straight forward. However, teeth, fortunately, are blessed with a host of stem cell populations.  This includes the pulp, which contains “human deciduous pulp stem cells” or hDPSCs.  These cells can be extracted from baby teeth.  Can they be tamed to regenerate the pulp?

A new paper from Science Translational Medicine by Kun Xuan and others have used hDPSCs to regenerate the pulp in two different animals.  However, this Chinese team did not stop there, since they turned around and tried hDPSCs in human patients.

In their animal model, implantation of hDPSCs into damaged teeth regenerated dental pulp with blood vessels and nerves.  However, it also with a layer that deposited dentine. In short, the regenerated pulp saved the damaged teeth.

On the strength of these results, Xuan and others enrolled 40 patients with pulp necrosis after traumatic dental injuries in a randomized, controlled clinical trial. In this trial, Xuan and his colleagues randomly assigned 30 patients to the hDPSC group and 10 to the group that received a traditional dental treatment called apexification.   Apexification materials like calcium hydroxide and mineral trioxide aggregates to form a calcified barrier in the lower parts of the tooth root to seal it and prevent it from further degradation. 

apexification.png

They lost four patients, whose teeth experienced new trauma and were lost.  In the 26 patients they examined after hDPSC implantation and 10 patients (10 teeth) after apexification treatment, Xuan and others found that hDPSC implantation, but not apexification treatment, regenerated the pulp tissue complete with blood vessels and sensory nerves at 12 months after treatment. hDPSC implantation also led to regeneration of sensory nerves in the pulp.

They further followed 20 of the hDPSC-implanted patients for 24 months to determine safety risks.  In these observations Xuan and others did not observe any adverse events.

This is a small study, but it is a very encouraging study.  It suggests that hDPSCs can regenerate whole dental pulp and may potentially revolutionize the treatment of tooth injuries due to trauma.  Larger studies are needed and all of this must be verified before commercialization of this treatment is possible, but it seems like a great start.

Building a Better CAR-T cell to Attack Solid Tumors


Chimeric Antigen Receptor T-cells or CAR T-cells are genetically engineered white blood cells that have been taken from a patient’s own blood, genetically engineered to express a receptor that can tightly bind to cancer cells, expanded in culture, and then re-administered into the patient’s blood.  These CAR T-cells then act like guided anti-cancer missiles that find, attack, and kill cancer cells.  The results of CAR T-cell treatments have been astoundingly successful, and the FDA has just approved several such treatments for specific cancers.  On May 1, the Food and Drug Administration (FDA) approved the CAR T-cell therapy tisagenlecleucel (Kymriah) for adults with certain types of non-Hodgkin lymphoma.  Last year, FDA approved another CAR T-cell therapy, axicabtagene ciloleucel (Yescarta), for the treatment of diffuse large B-cell lymphoma (DLBCL).

car-t20diagram20v2

CAR-T cell therapies are effective against blood cancers like lymphoma and leukemia, but when it comes to solid tumors, this treatment has been less effective.  Can CAR T-cell treatments be improved to attack solid tumors?  Research teams at Memorial Sloan-Kettering Cancer Center (MSKCC) and Eureka Therapeutics have bet that they can.  In a proof-of-concept study, MSKCC and Eureka Therapeutics scientists designed tumor-specific T-cells that express “checkpoint inhibitor” antibodies that protect the T-cell and allow it to evade the immunosuppressive tumor microenvironment found within a solid tumor.  The results of this study were published in the journal Nature Biotechnology.

Checkpoint inhibitors are monoclonal antibodies bind to cell surface proteins on white blood cells that are used by cancer cells to disengage the white cells from the tumor.  These checkpoint inhibitors, such as PD-1, when bound by cancer cells, cause the white blood cells to “forget” that they ever encountered the tumor.  This effectively permits the tumor to hide from the immune system.  Checkpoint inhibitors have successfully treated some solid tumors. In this experiment, the engineered CAR-T cells produced a single-variable fragment (scFv) PD-1 blocking antibody that is similar to already commercially available checkpoint inhibitor drugs.  This checkpoint inhibitor antibody innocuously binds to PD-1 and prevents the cancer cell engaging it.  This pulls back the tumor’s invisibility cloak and the CAR T cell recruits other neighboring immune cells to gang up on the tumor and kill it.

By using a mouse model, this study examined two different types of the anti-PD-1-expressing CAR-T cells; one of which targeted B-cell cancers and another that targeted solid tumors from in the ovary and the pancreas. ovarian and pancreatic cancer.  These groups discovered that their anti-PD-1-expressing CAR-T cells stayed near the tumor site longer and, once inside the tumor, they recruited other neighboring tumor-fighting cells to wake up and sock it to the tumor.

This very exciting finding may be foundational for future targeted therapies. “We can build CAR-T cells to secrete a variety of different molecules, tailored to the needs of the patient,” he says. “It’s not just limited to this one drug,” said Renier Brentjens, Director of the Cellular Therapeutics Center at MSK and one of the pioneers of CAR therapy.

 

Cynata’s Cymerus MSC Treatment Improves Cardiac Function Recovery in Preclinical Heart Attack Study


Cynata Therapeutics Limited, an Australian stem cell and regenerative medicine company, has announced the results of a preclinical trial in which it tests its Cymerus mesenchymal stem cell treatment in a preclinical heart attack model.

Cynata uses induced pluripotent stem cell technology to make large numbers of mesenchymal stem cells for therapeutic treatments.  To review, induced pluripotent stem cells (iPSCs) are made from body cells by means of genetic engineering and cell culture techniques.  Briefly, four different genes – OCT4, KLF4, SOX2, and c-MYC – are transfected into bodily cells.  Transient expression of these genes in regular body cells drives a small proportion of them (0.1%-0.5%) to undergo dedifferentiation into developmentally immature cells that resemble embryonic stem cells.  These embryonic stem cell-like cells, or iPSCs, will outgrow the other cells and can be successfully cultured in cell culture systems.  Once purified, cloned, and established as a viable cell line, the iPSC cell line can be grown to large numbers and differentiated into specific cell types.

Cynata has differentiated iPSCs derived from cells provided a healthy donor to make a recently identified precursor cell, known as a mesenchymoangioblast (MCA).  MCAs were first identified by Professor Igor Slukvin and his coworker from the University of Wisconsin-Madison. MCAs are early clonal mesoendodermal precursor cells that are the common precursor for both mesenchymal stem cells (MSCs) and endothelial cells, which are the main component of blood vessels. MCAs can also differentiate into pericytes and smooth muscle cells.

By making MCAs from iPSCs, Cynata seeks to overcome some of the largest hurdles for adult stem cell-based treatments, those being the dependence on donors for a steady supply of stem cells, the extensive variability of donated adult stem cells, the contamination of isolated adult stem cells with other cell types that do not have established therapeutic activities, and, probably most importantly, the limited scalability of stem cells from donors. Thus, in principle, Cynata’s Cymerus technology incorporates iPSC-derived MCA, which are used to make MCA-derived MSCs. This platform can potentially address the shortcomings of adult stem cell-based treatments, since iPSCs can proliferate indefinitely, and MCAs themselves can expand into extremely large quantities of MSCs. To quote the Cyanata web site; “Cynata should be able to manufacture all of the MCAs that it will ever need from a single Master Cell Bank of iPSCs – derived from a single donor.”

This most recent experiment was conducted by James Chong, Associate Professor at the Westmead Institute for Medical Research in Sydney, Australia, and colleagues. Chong and his coworkers induced heart attacks in three groups of rats (15 groups per group) and treated them four days later.  All the laboratory animals were assessed for 28 days after the heart attack (I wish they had observed them for longer periods of time). The rat groups consisted of three treatment groups: Group 1 received infusions of Cymerus MSCs, which were derived from iPSC-derived MCAs; Group 2 received MSCs from bone marrow; Group 3 was a placebo group that received infusions of buffer. All post-heart attack assessments were performed in a blinded manner, which simply means that the staff conducting the assessments had no idea which treatment the animal they tested had received.

The results of this study were rather encouraging.  The first category examined was “fractional shortening,” which is an estimate of the ability of the heart to contract effectively. Improvements in fractional shortening is indicative of recovery of the pumping function of the heart after a heart attack. Treatment with Cynata’s Cymerus MSCs resulted in an improvement in fractional shortening 28 days after the heart attack. Statistical comparisons showed that the Cymerus MSC-induced improvements were better than those observed in the placebo group (p=0.013) and the BM-MSC group (p=0.003).

The next assessment examined the effects of these treatments on left ventricular end-systolic diameter (LVESD). If, after a heart attack, the LVESD values are higher, then the heart is not contracting well.  However, reduced LVESD values are associated with improved cardiac function and correlated quite well with a reduced risk of further cardiac events. In this study, LVESD was lower in the Cymerus MSC group compared to those rats that had been treated with the placebo (p=0.054) and bone marrow-derived MSCs (p<0.001).

Finally, Chong and his gang examined the scar size as a proportion of the left ventricle size. For all three groups, there were no statistically significant differences between groups when it came to scar size as a proportion of the size of the left ventricle. It is possible that 28 weeks is far too short a time for the stem cells to produce any reduction in the size of the cardiac scar.  Therefore, further assessments of scar are ongoing.

To summarize, the Cymerus MSC treatments improved recovery of cardiac function post heart attack and reduced left ventricular end-systolic diameter (LVESD) compared to either placebo or bone marrow-derived MSCs, and further demonstrates the broad applicability of the Cymerus cell-manufacturing platform for clinical treatments.

In response to these positive results, Cynata’s Vice President of Product Development, Dr. Kilian Kelly said: “These very encouraging results add to a growing body of evidence showing that Cymerus MSCs may have an important role to play in the treatment of a wide range of diseases. There is still a huge unmet medical need associated with heart attacks, which cause over 8,000 deaths and more than 50,000 hospitalizations each year in Australia alone. We are optimistic about the potential benefits that Cymerus MSCs could bring to patients who experience these life-changing events.”

Steminent Biotherapeutics Inc Receives FDA Approval to Test Fat-Based Stem Cell Product to Treat Spinocerebellar Ataxia


Steminent Biotherapeutics Inc. is a biotechnology company based in Taipei, Taiwan, with subsidiary offices in San Diego and Shanghai. It is developing stem cell-based treatments for neurological conditions for which there are presently no treatment options.

The main product developed by Steminent is “Stemchymal.” Stemchymal consists of fat-based stem cells isolated from healthy donors. The cells are isolated from the fat (collected by means of liposuction), isolated, & standardized according to Good Manufacturing Practices that allows them to be administered to human patients. These fat-based mesenchymal stem cells contain a cornucopia of growth factors, cytokines, and other molecules that promote healing. They are also safe. Steminent scientists have shown that Stemchymal cells can be grown in culture for extended periods of time without becoming genetically altered. Stemchymal cells also neither form tumors in laboratory animals, nor elicit inflammatory reactions. Therefore, tissue matching is not required before administering them. Finally, Phase I clinical trials in human patients established the safety of Stemchymal when administered to people.

In Taiwan, Stemchymal has been approved for three different clinical trials. At the Taipei Veterans General Hospital, physicians are testing Stemchymal to treat osteoarthritis of the knee, spinocerebellar ataxia (a neurodegenerative condition), and vascular conditions. A recently approved application also allows testing Stemchymal to treat patients with diabetes mellitus.

In the United States, the Food and Drug Administration has “raised no objections” Steminent’s Investigational New Drug (“IND”) application that proposes to test Stemchymal as a treatment for polyglutamine spinocerebellar ataxia (“PolyQ SCA”).

Spinocerebellar Ataxias refer to a cluster of devastating, inherited neurodegenerative diseases that are relatively rare (between 2-7 per 100,000). These diseases are characterized by degeneration of the cerebellum, a part of the brain that regulates movement, and, sometimes, the spinal cord. Spinocerebellar ataxias (SCAs) are classified according to the altered genes that cause the disease. The symptoms of SCAs tend to include an uncoordinated gait, poor hand-eye coordination, and abnormal speech (dysarthria). There are no treatments for SCAs, and supportive measures are usually used.

Some SCAs are caused by the expansion of a portion of genes that encode stretches of the amino acid glutamine. Glutamine stretches seem to act as a flexible region that allows different portions of the protein to interact with each other.  When these glutamine stretches expand, the protein does not fold properly and aggregates, forming insoluble, toxic globules in the cell that cause cell death. Other mechanisms may be at work as well, such as mRNA toxicity, loss of protein function, or some other, as yet, uncharacterized mechanisms. There are more than 30 subtypes of SCA, and the following types of SCAs include poly-glutamine expansions: SCA1, SCA2, SCA3, SCA6, SCA7 and SCA17. The amino acid glutamine is encoded by the codons “CAG” and “CAA” stretches of these codons can cause DNA polymerase to slip, which causes the insertion of extra codons and expansion of the polyglutamine stretches.

The age of onset associated with PolyQ SCA disease patients can range from 20-50 years old. Not only are SCAs life-threatening diseases, but the extended physical handicaps imposed on the patient place a heavy burden on the patient’s family and healthcare providers.

As stated, there are no cures for SCAs, but Steminent has conducted a Phase I/II trial with SCA patients and showed that Stemchymal is safe for SCA patients. There were “no biological-related adverse effects observed in the 12-month follow-up. Additionally, patients seemed to improve while on Stemchymal. These functional improvements were maintained for up to 6 months.

In December 2015, the FDA designated Stemchymal as an Orphan Drug for the treatment of PolyQ SCAs. The Orphan Drug Designation grants “orphan status” to treatments of rare indications that affect fewer than 200,000 people in the U.S. This Orphan Drug Designation allows Steminent a seven-year window during they will enjoy “market exclusivity upon approval of Stemchymal® and other development incentives including tax credits for clinical research costs and Prescription Drug User Fee Act (PDUFA) fee exemption.”

Managing Director of Steminent USA, Dr. Jennifer Ho, said, “Our Phase II Stemchymal® SCA program includes double blinded, randomized, and placebo-controlled trials to evaluate Stemchymal® SCA for safety and evidence of efficacy for treating PolyQ SCA in three countries. The first of these Phase II trials is currently enrolling patients in Taipei, and now with FDA consent, we are very pleased to initiate this US orphan designated drug trial. ReproCELL, our Japan partner, has also submitted its CTN to the PMDA to assess Stemchymal® SCA in treating PolyQ SCA in Japan.”

Dr. Susan Perlman, Clinical Director, UCLA Ataxia Center, Professor of Neurology, UCLA, and Medical Director; National Ataxia Foundation, said of Steminent’s clincal trial, “as there are currently no approved treatments for this progressive, irreversible disease, we are encouraged by the possibility that Stemchymal® cell therapy may demonstrate safety and therapeutic benefit in these patients.” According to Dr. Perlman, “It is estimated that about 15,000 people in the USA suffer from PolyQ SCA disease.”

With FDA approval in hand, Steminent will prepare the US trial sites and commence patient enrollment.

Aegle Therapeutics is Awarded IND to Test Extracellular Vesicles from Stem Cells in Burn Patients


Aegle Therapeutics is a Miami, FL-based biotechnology company that has taken a completely novel approach to regenerative medicine.  Aegle Therapeutics has developed new techniques to isolated extracellular vesicles made by cultured stem cells.  Specifically, Aegle Therapeutics isolate extracellular vesicles from bone marrow-based mesenchymal stem cells for therapeutic purposes.

Scientists at Aegle Therapeutics have shown that standard protocols used to isolated extracellular vesicles tend to badly damage them.  If these damaged extracellular vesicles are administered to injured animals, they tend to induce inflammation and fail to promote healing.  Aegle has demonstrated this very fact by administering extracellular vesicles (EVs) isolated by standard protocols to pigs suffering from skin injuries.  These damaged EVs did not promote healing and made the injuries worse.  However, if similarly, injured pigs were administered undamaged, whole EVs isolated with Aegle Therapeutics’ proprietary protocols, they not only accelerated healing, but they significantly decreased scarring and promoted the formation of blood vessels and hair follicles and nerve regeneration.

Aegle’s isolation process is also easily scalable and low-cost.

Aegle Therapeutics has used their whole EV preparations to treat severe dermatological disorders, with a specific focus on the treatment of burns. In May 2018, Aegle announced that the US Food and Drug Administration (FDA) approved an Investigational New Drug (IND) application. This IND will examine the use of whole EVs from mesenchymal stem cells to treat severe second degree burn patients. This is an open label dose escalation study, which means that the patients and their physicians will know that they are being treated with the experimental product, but randomly-assigned groups of patients will receive gradually increasing doses of the EVs. This clinical trial will test both safety and efficacy (a Phase 1/2a clinical trial) of Aegle Therapeutics’ lead product, AGLE-102. This clinical trial will enroll burn patients at several U.S. sites.

According to the founder and Chief Science Officer of Aegle Therapeutics, Evangelos Badiavas, M.D., Ph.D., “We are excited to be moving our EV therapy into the clinic to treat burns, an indication with a substantial unmet medical need. We believe this product has the potential for functional regeneration and organization of complex tissue structures that can enhance healing, reduce scarring, minimize contraction and improve overall cosmesis. Currently, patients with burns suffer scarring, disfigurement, loss of mobility and chronic pain. There’s a real need for better therapies.”

According to Shelly Hartman, Chief Executive Officer of Aegle, “This achievement is an important step as the company launches a Series A capital raise in 2018 to fund its clinical development.”

Aegle Therapeutics is also developing another product, AGLE-103 for the treatment of a genetic skin condition called epidermolysis bullosa (EB), which causes the skin to be fragile and blister.

Rexgenero Treats Its First Patient In Phase III Clinical Trial of Bone Marrow-Based Critical Limb Ischemia Treatment


According to their website, Rexgenero is a “regenerative medicine company and developer of advanced cell-based therapeutics for the treatment of serious diseases that are poorly treated with existing therapies.”   The head office of Rexgenero is in London, but their Research and Development laboratories are in Seville, Spain.  They also have a United Kingdom office in Brighton, which is a town with which I have some familiarity, since I lived there at one time in my life.

Rexgenero has focused on developing regenerative products from bone marrow cells.  In particular, they have used bone marrow-derived mononuclear cells (BM-MNCs).  BM-MNCs are extracted from the patient’s bone marrow after a bone marrow aspiration.  To isolate the mononuclear fraction, the white blood cells fraction from bone marrow is usually isolated by centrifugation with a material called Ficoll.  The pelleted material is the mononuclear fraction and contains a potent mixture of lymphocytes, monocytes, mesenchymal stem cells, hematopoietic progenitor cells, and other less well-characterized cell populations.

BM-MNCs

Another component of bone marrow mononuclear cells is endothelial progenitor cells (EPCs), which give rise to the walls of blood vessels.  When locally infused locally at the site of diseased vascular tissue, a well-processed mononuclear fraction can potentially form new blood vessels and restore tissue that was formerly starved for oxygen (see Haider, KH, Aziz S, and Al-Reshidi MA, Regenerative Medicine, 2017 12(8):969-982 for a review).

A bone marrow-based product developed by Rexgenero, called REX-001, has been used in human clinical trials to revascularize patients with a rather nasty condition called Critical Limb Ischemia (CLI).  CLI occurs when the blood vessels that feed and nourish an arm or leg are severely damaged or obstructed.  This results markedly reduces blood flow to the limb and the oxygen-deprived tissues can begin to die off, which causes excruciating pain, and disfiguring skin ulcers or sores.

CLI skin ulcer

These ulcers can become infected, gangrenous, and may require debridement or, in the most severe cases, limb amputation (yikes!).

Can REX-001 administration treat patients with CLI?  In an earlier Phase II clinical trial, which was completed in 2016, REX-001 was administered to over 100 patients in three clinical trials.  The results were rather encouraging. Patients who had severe ischemic pain at rest without skin ulcers (Rutherford scale in category 4), or resting pain with skin ulcers (category 5) were treated with REX-001 for 12 months.  At the end of 12 months, most patients (the website does not say what percentage of patients) in both patient populations were devoid of CLI and showed significant improvement in their clinical condition, as assessed by changes in Rutherford category.  Patients showed complete ulcer healing and alleviation of rest pain.  Angiographic imaging of treat patients definitively showed that REX-001-treated patients had extensive new networks that blood vessels that had sprouted.  It is reasonable, in my view to suspect that these new blood vessel networks in the limb were responsible for the corresponding improvement in patient’s clinical condition.

REX-001-induced new vasculature
Angiograms showing blood vessels prior to treatment (left) and after 6 months following treatment with REX-001 (right)

Rexgenero has recently announced the treatment of its first patient in a Phase III clinical trial that will evaluate REX-001, in patients with CLI and Diabetes Mellitus (DM).  In these two placebo-controlled, double-blind, adaptive Phase III trials, patients with CLI and DM with severe ischemic limb pain will be treated with REX-001 or a placebo to assess the efficacy and safety of REX-001 in the relief of CLI-associated resting limb pain.  In a second leg to this Phase III study, CLI patients with ischemic limb pain and skin ulcers (Rutherford stage 5) will be treated with REX-001 or a placebo to ascertain the efficacy and safety of REX-001 in the healing of CLI-induced skin ulcers. The relief of pain and the complete healing of ulcers are the primary endpoints of this clinical trial and amputation-free survival is the secondary endpoint in both legs of the study.

The European Medicines Agency (EMA) has fully endorsed the design of both legs of the trial, and this includes the target patient population and primary endpoints.  Clinical improvement in CLI patients increases the probability of successful treatment. Rexgenero also plans to enroll a total of 138 patients at approximately 35 clinical sites in Europe with first interim results expected in circa 18 months’ time and full data in 2020.

Joe Dupere, Rexgenero’s CEO, said “We are extremely pleased to announce the first patient infusion in our Phase III program with REX-001, which if successful could significantly improve the treatment of patients with CLI.”  He continued: “The program has been designed following advice from the EMA and in close collaboration with our Scientific Advisory Board. CLI is a medical condition with a clear need for new improved treatment options. Our goal is to bring innovative cell, gene and tissue therapies to the market addressing high unmet needs which cannot be treated with available therapies. We believe that REX-001 has the potential to be one of the first effective cell therapy products available for patients with CLI.”

This is definitely one clinical trial to keep an eye on.  If bone-marrow-based cell preparations can help patients sprout new blood vessel networks, there might be applications for other medical conditions as well, including cardiac ischemia, intestinal blood vessel blockage, and liver disease too.