The Mission: Targeting Tuberculosis and other Infectious Diseases with Liposomal Nanotherapeutics

Executive Summary: Akagera Medicines is developing novel liposomal formulations of antibacterial drugs to treat tuberculosis and other infectious diseases. The company was founded in 2018 in Kigali, Rwanda. It is well-funded, majority-owned by the people of Rwanda, registered as a Delaware corporation, and has laboratories in Boston and San Francisco. Akagera registered a 100%-owned subsidiary in Kigali in 2022 to do manufacturing and clinical trials in the future. Founding board members and advisors include Ambassador Dr. Albrecht Conze, Dr. Paul Farmer, Dr. Donald Kaberuka, and Dr. Anne Lenaerts.

Akagera Medicines has developed and patent protected a series of novel liposomal formulations of antibacterial drugs for treating infectious diseases. The mechanism of action (MoA) for this new class of infectious disease drugs includes increased delivery and uptake of liposomal nanoparticles that contain potent, antibacterial drugs — into macrophages responsible for phagocytosis.

Liposomal therapeutics represent a well-validated platform of drug delivery systems that are used for the treatment of a wide range of diseases. They include systemic fungal infections, mycobacterium avium, and cancers. They are utilized to alter the biodistribution of the encapsulated drug and the exposure profile for the drug, and impact both the efficacy and the toxicity (the therapeutic index) of the active drug.

The company has developed a therapeutic for MRSA, and vaccine candidates for Tuberculosis, Lassa Fever, HIV, RSV, and Influenza. The vaccine candidates are being developed in close partnership with THE GATES FOUNDATION, the National Institute of Health (NIH) – Vaccine Research Council (VRC), the Center for Epidemic Preparedness Innovations (CEPI), and a public pharmaceutical company.

The Need: Drug-resistant forms of TB are increasing among the poor

The team at Akagera Medicines formed with an explicit moral purpose. Perhaps one out of every seven persons who ever lived has died from TB. Three large pharmas have left the market in the last five years because their priorities do not allow them to pursue a solution to this disease. The drug-resistant forms of the disease are increasing among the poor throughout the world due to the lack of screening, high costs, low compliance, and long treatment times.

Each year, more than ten million new cases of TB are reported, almost two million people died from it, and 400,000 of them are children.

It surprises many people in Europe and North America that TB remains one of the great scourges in human history. One out of every three people in the world is infected with latent or sub-clinical TB, and scientists predict that 10% of those will manifest the disease as age and other illnesses compromise their immune systems.

TB once affected every stratum of society, but it now afflicts the most vulnerable populations. The incidence of drug-resistant TB is on the rise because the health-care systems of poor countries lack the resources to screen for TB and to help patients comply with their therapies.

Tuberculosis impacts superpower politics, north-south economics, and wildlife

Six countries – India, Indonesia, China, Nigeria, Pakistan, and South Africa – account for 60% of all reported TB cases. Russia may be willfully underreporting its TB burden, and some African countries do not know how many of their citizens are infected.

The fight against TB remains more important than ever. An increase in tuberculosis in China could existentially challenge the leadership, and tear the country apart with the concomitant problems for the global economy.

Tuberculosis could place increased social pressure on the already poor relations between India and Pakistan, two nuclear powers who mistrust each other. No African nation can afford the traditional, long, and expensive protocols that TB treatments now require, and those expenditures displace investments in education, infrastructure and security. Haiti, one of the United States of America’s closest neighbors, is on the brink of collapse partially because the health of their citizens is declining due to TB and other infectious diseases.

Finally, TB is a direct threat to wildlife throughout the world. This is especially true of our closest animal relatives who are increasingly exposed to eco-tourists from around the world. They may share the same vulnerabilities to TB as human beings.

The Approach for MDR-TB: Engineer novel, small-molecule drugs encapsulated in liposomes

The Founders of Akagera Medicines were involved with the invention, development, and subsequent FDA approval of a liposomal drug. It was the first drug approved in that line of therapy.

Akagera Medicine scientists propose to use their considerable experience in drug delivery, together with their experience in medicinal chemistry, to develop safe and highly efficacious treatment regimens with less frequent and shorter treatment durations for multidrug resistant (MDR) and extreme drug resistant (XDR) tuberculosis. To this end, Akagera Medicine scientists have engineered a series of novel small molecule drug-candidates against two different tuberculosis bacterium targets, mycobacterial ATP synthase (diarylquinolines) and bacterial protein synthesis inhibitors.

The United States Patent Office has described the technology of Akagera Medicines as "novel”, possessing “wide industrial applicability”, and having “no prior art”. The USPTO invited Akagera Medicines into “an expedited process”. A member of Akagera Medicines’ Science Advisory Board, a scientist with more than two decades of industry experience said, "I have never seen such a clean bill of health from the United States patent office.”

These novel, small molecule payloads were engineered using the most advanced understanding of structure/activity relationships for these classes. Akagera Medicines novel inhibitors can be stably encapsulated in liposomes, and retain or improve upon the potency/selectivity of the most advanced generation of inhibitors against each target (i.e. modifications of second or third generation inhibitors). The molecules are also being screened for CYP450 induction and inhibitory activity to ensure their use with HIV antiretrovirals, and for activity in resistant strains of mycobacterium tuberculosis to first line therapies.

In Vitro Activity

A panel of rationally engineered small molecules have already been evaluated for activity in vitro against drug-sensitive tuberculosis strains, and for potential toxicity against normal human kidney and liver cells.

The lead drug-canddiates have activity that is between 16-67 fold more potent than the standard of care used in MDR and XDR tuberculosis treatment. These candidates show excellent selectivity over human hepatocyte or kidney cell lines. There is more than a thousand-fold difference in sensitivity to the drug-candidate compared to that in two drug-sensitive tuberculosis strains, and equal activity in multiple strains of TB resistant to first-line therapies.

These drug-candidates have been successfully formulated in liposomes and have long-circulating pharmacokinetics and very stable drug association while in the circulation (e.g. less than 10% drug release over 24 hours).

These formulations were tested for efficacy in the Kramnik mouse model, which resembles human pathology. This model is characterized by pulmonary caseous necrotic lesions or granulomas, and contains both intracellular and extracellular mycobacteria. The lead formulations demonstrate an excellent toxicity profile in pre-clinical chronic treatment studies.

Akagera Medicines is represented by Gunderson Dettmer for corporate law, Greenberg Traurig for Intellectual Property Law, Dentons Europe LLP for Europe and Multilateral Institutions, Woodruff Sawyer and the CHUBB Group for Insurance, and Armanino LLc for accounting services.

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