open a new path for pharmaceutical R&D

In February, a new kind of pharmaceutical company was launched, backed by $ 250 million in Series A funding and taking a novel approach to R&D. Founded by life science venture capital firm Medicxi, Centessa Pharmaceuticals is made up of ten biotech start-ups from the company’s funding portfolio.

The company now consists of four clinical stage programs, two of which are in advanced clinical development, and more than ten additional programs covering high unmet need in oncology, hematology, immunology, neuroscience and rare diseases. Each subsidiary team works on a single program or organic pathway, rather than several small projects, which Centessa says will help make it a success.

In a public statement, Centessa CEO Saurabh Saha said, “This approach encourages an environment in which scientific teams are encouraged to maintain an unwavering focus on advancing drugs to key inflection points to be monitored on. the basis for data-driven decisions.

The company hopes that by giving each subsidiary the flexibility to deploy capital as it sees fit, teams will be uniquely motivated to continue researching drugs and indications, without being weighed down by the operational limitations of other companies. pharmaceuticals.

Centessa’s Chairman of the Board, Frencesco De Rubertis, said: “Centessa’s vision is to build a pharmaceutical company with a single operational framework that aims to reduce some of the main R&D inefficiencies that mainstream pharmaceutical companies face. due to structural constraints.

“Our operations will be guided by an asset-centric approach, in which each Centessa subsidiary will focus solely on the execution of its programs under the supervision of Centessa’s highly experienced management team. The ambition to apply asset centricity on a large scale is to be able to provide patients with life-changing drugs with improved efficiency by increasing the productivity of R&D.

GlaxoSmithKline abandoned a similar approach to R&D in 2017 when current CEO Emma Walmsley took office, after limited success. At launch, the Scientific Director of Centessa was Moncef Slaoui, a veteran of the pharmaceutical industry who had worked at GSK for 30 years. Slaoui led R&D at GSK from 2006 to 2014, where he worked to reorient the organization’s sprawling R&D operations into smaller, more focused units.

However, Slaoui was dismissed from his post at Galvani Bioelectronics, a majority-owned joint venture by GSK, in March of this year after an independent investigation revealed that he sexually harassed a GSK employee several years ago. Slaoui has since resigned from Centessa as well.

Centessa’s subsidiaries are: ApcinteX, Capella BioScience, Janpix, LockBody, Morphogen-IX, Orexia Therapeutics, Palladio Biosciences, PearlRiver Bio, Pega-One and Z Factor.

Medical technology takes a closer look at some of the notable start-ups that make up the portfolio.

ApcinteX

The University of Cambridge spin-out, ApcinteX, aims to develop a new treatment for hemophilia, where patients are given a monthly subcutaneous injection instead of regular intravenous infusions.

Hemophilia is an inherited disease in which the blood does not clot properly, causing bleeding that does not stop. Most cases of hemophilia are severe and require preventive treatment, involving regular injections of artificial blood thinners.

The disease affects around half a million people worldwide, many of whom have limited access to treatment and thus would find monthly treatment particularly beneficial.

ApcinteX has developed a drug called SerpinPC, which may be able to provide safe and convenient treatment for the disease. In February, he revealed the results of the first part of his ongoing trial, which demonstrated a 55% reduction in all bleeding and a 72% reduction in spontaneous joint and muscle bleeding in subjects.

This first part of the study followed only 12 subjects, but the second part is underway, with 23 participants who are expected to receive SerpinPC by monthly subcutaneous injection for six months. The results are expected in the second quarter of this year.

Morphogen-IX

Morphogen-IX, a Cambridge University spin-off company, is focused on the development of bone morphogenetic proteins (BMPs) for the treatment of pulmonary arterial hypertension (PAH). PAH is a rare progressive disease characterized by high blood pressure in the pulmonary arteries for no apparent reason, ultimately leading to heart failure and death when the blood vessels in the lungs narrow and close.

BMPs are a group of growth factors capable of inducing the formation of bone and cartilage in the body. Inactivating mutations in the bone morphogenetic protein type II receptor (BMPR-II), a membrane protein that binds to BMP9, is the most common cause of PAH. BMP9 is normally produced in the liver and circulates in the blood to maintain the integrity of the endothelial cells that line the internal surfaces of blood vessels, including the lungs.

This is something that Morphogen-IX’s lead candidate aims to target. In preclinical models of PAH, supplementation with BMP9 levels has been shown to prevent and reverse disease. Existing therapies for PAH focus primarily on reversing blood vessel constriction, but Morphogen-IV has developed MGX292, a protein variant of BMP9. MGX292 has the potential to restore the protective signaling pathway necessary to maintain cell integrity in the lungs and prevent cell death in blood vessels.

Orexia Therapeutic

People with type 1 narcolepsy have low levels of a chemical called orexin, also known as hypocretin, a neurochemical that helps regulate wakefulness and REM sleep.

The disease, usually associated with excessive daytime sleepiness and uncontrollable sleep cravings, also causes cataplexy, a sudden loss of muscle tone while awake, often triggered by strong pleasurable emotions.

Orexia Therapeutics is working on both oral and intranasal therapies targeting the orexin 2 receptor, where they have the potential to directly treat the underlying pathology of orexin neuron loss. These therapies also have the potential to help treat other neurological conditions characterized by excessive daytime sleepiness.

Orexia is a spin-off of the Japanese company Sosei Group Corporation, created in February 2019 by Sosei and Medicxi and now merged into Centessa.

Palladio Biosciences

Palladio has now reached phase 3 of the development of lixivaptan, a treatment for autosomal dominant polycystic kidney disease (ADPKD). ADPKD is a genetic disease characterized by the growth of numerous cysts in the kidneys, which usually begins between the ages of 30 and 40 and tends to get worse over time. It’s the 4e leading cause of kidney failure in the United States and is a fatal, chronic and progressive disease.

The Palladio ALERT study, designed to assess the safety of lixivaptan in ADKPD patients who previously discontinued tolvaptan treatment due to liver toxicity, administered its first patient in November. Patients included in the study will be treated with the drug for up to 58 weeks, with the goal of establishing its safety profile.

Leachaivaptan is functionally equivalent to tolvaptan, but to date it has not exhibited the associated hepatic toxicity.

The drug was originally developed as a treatment for an electrolyte disorder that affects patients with heart failure, but was rejected by the United States Food and Drug Administration in 2012. The rights to the molecule have passed through. several different hands before Chiesi allowed it to Palladio in 2017.

Z factor

The third Cambridge University spinoff to join Centessa is Z Factor, a company that develops drugs to treat alpha-1-antitrypsin deficiency (AATD).

People with the genetic condition lack a protective chemical in their bodies called alpha-1-antitrypsin due to a defect in the A1AT gene that codes for it, which leads to lung and liver problems. The most common mutation that causes AATD is called a Z mutation, which disrupts normal protein folding.

Z Factor founder Professor Jim Huntington explains, “Low levels of properly folded A1AT in the lungs lead to the development of emphysema in almost all patients with AATD. At the same time, the accumulation of Z-A1AT polymers in the liver can cause liver disease, sometimes manifesting as liver failure in newborns and more commonly cirrhosis and liver cancer as carriers of this age of mutation.

The Z Factor tram has designed drugs that could correct defective A1AT folding in people with AATD and prevent the development of associated diseases.

In August last year, the company announced that the first human volunteer had received a dose of ZF874, a new compound it had developed. The compound acts as a molecular patch for the defective protein, allowing it to fold properly. This relieves the liver burden from polymer build-up and provides fully functional Z-A1AT in the circulation to protect the lungs.

In mice genetically engineered to express human Z-A1AT in their liver, oral doses of ZF874 significantly increased levels of properly folded proteins in the blood and cleared the buildup of misfolded proteins in the liver. .


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About Hector Hedgepeth

Hector Hedgepeth

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