Alizé Pharma 3 (Alizé 3) is the brainchild of Thierry Abribat, a French biotech entrepreneur who is trained as both a doctor of veterinary medicine and as a research neuroendocrinologist. Thierry previously founded two other Alizé companies (Alizé Pharma and Alizé Pharma 2), where he brought single assets into the clinic and then sold the companies to pharma (Jazz Pharmaceuticals (2016) and Millendo Therapeutics (2017)). In late 2017, Thierry started Alizé Pharma 3 with a compound developed in close collaboration with Professors David Clemmons and Cliff Rosen, and licensed from the University of North Carolina and the University of Maine. The potential drug is a small peptide derived from insulin-like growth factor-binding protein factor 2 (IGFBP-2), a key regulator of glucose metabolism. The molecule can regulate glucose homeostasis, adipose tissue deposition, and bone metabolism to treat a spectrum of metabolic dysregulations, with current focus on severe insulin-resistance syndromes such lipodystrophies and insulin receptoropathies. The company initially operated in stealth mode for 18 months, supported by a small seed capital round, primarily from Thierry’s prior investors in Alizé Pharma and Alize Pharma 2. During this time, Thierry decided he wanted a different model for Alizé 3, a larger company with a balanced, portfolio of programs in rare endocrine and metabolic disease, and so he sought a strong scientific collaborator.
Fortunately for Thierry, he had an excellent idea of whom he wanted to work with, a scientist named Mike Culler, who Thierry had known for 25 years. Mike has spent his entire career working on various topics in metabolic and endocrine disorders, with a specific focus on peptide hormones and therapeutics. Trained as a neuroendocrinologist, Mike had a 12-year academic research career at Tulane University School of Medicine and the NIH before joining Johnson & Johnson, where he led discovery research exploring the interplay between the endocrinology and the immune systems. After J&J, he joined Ipsen, a French pharmaceutical company where he was head of endocrinology research and led multiple drug discovery programs, including five that reached the clinic. After departing from Ipsen, Mike and Thierry began discussing teaming up to build Alizé 3. During this time, Mike also met with Partners Innovation Fund (through an introduction from one of PIF’s portfolio companies), and talked about opportunities within the broad Partners research portfolio. Meredith Fisher, a partner at PIF, sent Mike several opportunities to consider, including a unique, long-acting parathyroid hormone (PTH) analog for treatment of hypoparathyroidism that was ~12 months from IND. Mike knew this therapeutic area well, having already led the discovery program for a PTH analog for osteoporosis (abaloparatide: Tymlos®), and after reviewing the data package in collaboration with Thierry, they decided it would be a great fit for Alizé 3.
Hypoparathyroidism is a rare condition caused by the absence or abnormally low levels of parathyroid hormone. Most cases of hypoparathyroidism are inadvertently caused by damage to the parathyroid glands during thyroid surgery. PTH maintains blood calcium levels within a tight physiological range by releasing calcium stores from the bone, preventing the loss of calcium in the urine, and by producing the active form of vitamin D to allow intestinal calcium absorption. Individuals with hypoparathyroidism are unable to regulate their blood calcium and have abnormally low circulating calcium levels (known as hypocalcemia). Hypoparathyroidism patients suffer through a myriad of body-wide symptoms ranging from mild to debilitating (neuromuscular, mental issues, etc.) to potentially life-threatening, including cardiac arrest and seizures, and resulting in repeated emergency room visits to deal with crises. There are about 80,000 patients in the US with chronic, permanent hypoparathyroidism. The goal of therapy is to replace the function of PTH to regulate calcium. The current standard of care is large dose supplementation with calcium and vitamin D, but these treatments do not prevent the excess loss of calcium in the urine, which is toxic to the renal tissues and can result in chronic renal impairment and kidney stones. A second therapeutic approach is the administration of the natural PTH hormone; however, due to its very short half-life, it too does not prevent the excess loss of calcium through the kidney. The ideal treatment would be a long-acting PTH analog that restores normal resorption of calcium by the kidney to allow restoration of steady, circulating levels of calcium in the blood, and does not induce drug-related adverse effects.
Fortunately, such an approach has been investigated by a group of researchers in MGH’s endocrinology department that has studied PTH physiology for multiple decades. The team originally lead by John Potts, and that now includes Thomas Gardella, Harald Juppner, Robert Neer, Henry Kronenberg, and Michael Mannstadt, were the first to elucidate the structure of the 84-amino acid natural PTH, to develop a truncated version of the natural hormone now used to treat osteoporosis, and that discovered the PTH1 receptor. Recently, through the work of Tom Gardella and collaborators, it was demonstrated the PTH receptor exists in two conformations: RG and R0. Compounds that selectively bind to the RG conformation, initiate a brief biological response that produces a short burst of calcium release, making RG a valuable target for the treatment of osteoporosis. Compounds that selectively bind to the R0 conformation lead to a greatly prolonged biological response (lasting for hours to days), and as such, R0 is the ideal target for generating the long-duration response needed to treat hypothyroidism. Through these efforts, the MGH team recently developed a PTH analog that is highly potent and selective for the R0 conformation. This long-acting parathyroid hormone (LA-PTH) is designed for subcutaneous injection and displays all the in vivo properties desired in a therapeutic for treating hypoparathyroidism.
These data compelled Alizé 3 to seek a license to the LA-PTH asset. Based on their scientific expertise, business acumen, and with support from PIF as well as the MGH team, they were selected as the licensee. The LA-PTH (now AZP-3601) program became Alizé 3’s lead asset, and on the basis of this compound, and the IGFBP-2 mimetic, Alizé 3 raised $75M in a Series A round in July with PIF participating alongside LSP, Novo Ventures, OrbiMed, Pontifax, Kurma Partners, BPI France, Sham Innovation Santé and Crédit Agricole Création. This was one of the biggest series A rounds ever raised in Europe. With this investment in hand, the company is ramping up quickly. They are hiring, building their clinical team, and continuing to evaluate additional opportunities to treat rare endocrinology diseases. They plan to be in the clinic with their first trial of the LA-PTH asset in 2020, with the IGFBP-2 asset following closely behind. We at PIF are excited about our investment in Alizé and the opportunity to support a great team, a great asset, and great research. Bonne chance, Alizé!