Biotech firms on the shoulders of giants

Seqens’s facility in Ville​neuve-la-Garenne, France, was established almost 130 years ago to extract the malaria treatment quinine from the bark of the cinchona tree. It is considered one of the oldest pharmaceutical chemical sites in the world.

Today, Villeneuve is making the main ingredient in one of the world’s newest drugs: Mithra Pharmaceuticals’ oral contraceptive, Estelle, approved by the US Food and Drug Administration on April 15 and now marketed by Mayne Pharma. The ingredient is estetrol, a natural estrogen touted as having a better side-effect profile than the estrogen in most contraceptives. Synthesizing it for use in a drug, though, is no easy task.

Like the site where estetrol is being made, the story behind the new drug is many years old. Estetrol was first identified in 1965 by Egon Diczfalusy, a reproductive endocrinologist at the Karolinska Institute. But Diczfalusy didn’t pursue its potential as a contraceptive, says Jean-Manuel Fontaine, Mithra’s vice president of external and scientific affairs. “It was kind of shelved for 40 years,” Fontaine says.

Estelle at a glance

▸ Active ingredient: Estetrol

▸ Discovered: 1965 by Egon Diczfalusy; conceived as a therapeutic around 2000 by Herjan Coelingh Bennink

▸ Indication: Pregnancy prevention

▸ Innovation: An estrogen with fewer side effects than current products

▸ Status: US Food and Drug Administration approval in April 2021

Estetrol, also known as E4, was revived around the year 2000 by Herjan Coelingh Bennink, an executive at the contraceptive maker Organon. “He was convinced that E4 would be a fantastic estrogen to explore as a therapeutic agent,” Fontaine says.

Bennink was struck by the high concentration of E4 in fetal blood at 9 weeks of pregnancy. “If at the ninth week of gestation you have such high concentrations at such a delicate moment of life, it’s got to be safe” was Bennink’s reasoning, Fontaine says.

The leading oral contraceptives today are based on ethinyl estradiol, a synthetic derivative of another estrogen, estradiol. Like Estelle, many also include the progestin drospirenone. Current products are effective at preventing pregnancy, but they carry the risk of liver damage and blood clots and are associated with an increased risk of breast cancer. Moreover, ethinyl estradiol is considered an endocrine-disrupting chemical that, after people excrete it, can build up in creatures living in rivers and oceans. Mithra says estetrol doesn’t accumulate in living organisms.

Bennink left Organon soon thereafter to form his own company, Pantarhei Bioscience, which launched studies on estetrol in women’s health and oncology applications. In 2009 the company formed a contraceptive-focused joint venture with Mithra; by 2015, Mithra had acquired full rights to estetrol for contraceptive and menopausal uses. Pantarhei continues to develop the molecule for oncology and veterinary use.

Mithra had picked Cambridge Major Laboratories’ ChemShop unit in Weert, the Netherlands, to manufacture estetrol in the early days of development. Output was enough for preclinical studies and Phase 1 clinical trials, but yields were low. “There was a need to find a different provider to get a better yield,” Fontaine says. Mithra focused its hunt for another supplier on western Europe to ensure intellectual property protection and rapid response.

Meanwhile, executives at Seqens had their eyes on estetrol. A drug services and specialty ingredient firm based in France, Seqens operates 24 plants and seven R&D centers across Europe, North America, and Asia. Its pharmaceutical synthesis business includes facilities acquired from several long-standing players in the business, including PCAS and Uetikon in Europe and PCI Synthesis in the US.

Philippe Clavel, Seqens’s vice president for pharmaceuticals, says his team saw estetrol as a good fit. The company had experience making another hormone at its site in Aramon, France, and the Villeneuve facility likewise had the equipment and health safeguards needed to produce a compound considered highly potent. Mithra apparently agreed. It chose Seqens out of the 10 contract manufacturers it was considering, and in 2012 the two firms signed an agreement covering production of estetrol for clinical trials.

Estetrol is not an easy molecule to manufacture, according to Fontaine and Clavel. Development of the industrial-scale process now being carried out in Villeneuve took about 4 years, mostly at Seqens’s R&D center in Porcheville, France, Clavel says.

A production campaign, which takes several months, starts with a phytosterol extracted from soybeans. Getting to estetrol requires eight synthetic steps plus associated purifications. Multiple protection and deprotection steps are needed, Clavel says, as are tricky oxygenation reactions. All the while, both the stereochemistry and the molecule’s four hydroxyl groups must be maintained.

Seqens first established production at an existing unit in Villeneuve that it modified for the purpose. But as the contraceptive cleared hurdles in clinical trials and regulatory approval looked more and more likely, Clavel and his team took stock. Estelle could eventually require multiple metric tons per year of estetrol, more than the modified facility could make. They realized they would have to step up to keep Mithra as a customer.

So Seqens decided to spend roughly $35 million on a brand-new facility in Villeneuve dedicated to estetrol production. The firm began construction in the second half of 2018 and completed it in mid-2020. Last August, the president of France, Emmanuel Macron, visited Villeneuve for the new facility’s inauguration. Seqens is validating the facility now, Clavel says, in anticipation of beginning commercial production later this year.

Clavel says Macron’s visit demonstrates the French government’s understanding that more and more pharmaceuticals are considered highly potent and that the ability to make them is key to keeping drug production alive in the country. “France has very few manufacturing facilities of this type,” Clavel says. “What is at stake is France’s and Europe’s sovereignty in manufacturing highly active APIs.”

Both Clavel and Fontaine say the new facility in Villeneuve may not be enough if Estelle and estetrol live up to their potential. In addition to the US, Estelle has been approved in the European Union and Canada. KBC Securities, an investment firm that covers Mithra, says Estelle could bring in nearly $1.2 billion in sales by 2031, capturing 8% of the global oral contraceptive market.

And Mithra sees potential for estetrol in other applications as well. “Next is menopause, where a safer estrogen is even more important,” Fontaine says. The company is conducting clinical trials of an estetrol-based product for relieving menopause symptoms and plans a product for perimenopause, also known as menopause transition.Beyond reproductive health, Mithra is researching the use of estetrol in wound healing and reducing neonatal encephalopathy. And it is even conducting clinical trials of estetrol to help hospitalized patients with COVID-19 recover.

Anticipating continued growth in demand for estetrol, Mithra is studying the best way to make it. “We have a whole department dedicated to the synthesis of E4,” Fontaine says. Among the scientists’ goals are production routes with fewer steps and syntheses that incorporate both chemical and biotechnological transformations.

Fontaine also wants to diversify Mithra’s supply of estetrol beyond the Villeneuve complex. Seqens and Mithra are already discussing the idea of establishing Seqens’s Aramon site as a backup, Clavel says, and Seqens is prepared to build another dedicated facility that would be ready by 2027 or 2028.

Fontaine says Mithra is looking at a range of companies for its future manufacturing needs, but he says he’s committed to his relationship with Seqens. “It’s an important contract for them and for us,” Fontaine says. “We’re going to be working together for many years.”

On Friday, Jan. 22, at around 3:00 p.m. on the US West Coast, Robert Huizinga celebrated a milestone. He received word that the US Food and Drug Administration had approved voclosporin, a drug developed by Aurinia Pharmaceuticals for the treatment of adults with lupus nephritis. To Huizinga, Aurinia’s executive vice president of research, the FDA approval was the culmination of more than 15 years of work.

“It was immensely gratifying,” he recalls. “I will remember that day for the rest of my life.”

Voclosporin was discovered in the mid-1990s at Isotechnika Pharma, which merged with the Canadian biotech firm Aurinia in 2013 and took the firm’s name. Huizinga led the clinical development program for voclosporin before and after the acquisition—including a shift in the synthesis from one that yielded racemates to one that yields a single trans isomer. The result was the first FDA-approved oral therapy for lupus nephritis.

Lupkynis at a glance

▸ Active ingredient: Voclosporin

▸ Discovered: Mid-1990s by Isotechnika Pharma scientists

▸ Indication: Lupus nephritis

▸ Innovation: An analog of cyclosporine in which a single amino acid has been modified

▸ Status: US Food and Drug Administration approval in January 2021

Now Aurinia is gearing up to take the drug to market under the trade name Lupkynis. In December, the company entered an agreement with the giant contract manufacturer Lonza, which will build a dedicated plant for voclosporin in its small-molecule active pharmaceutical ingredient (API) facility in Visp, Switzerland.

Lupus is a chronic autoimmune disease that, if poorly controlled, can lead to lupus nephritis, a dangerous kidney condition. Lupus disproportionately affects women and people of African or Asian background. In the US, 1 out of every 250 African American women will develop lupus, according to a 2015 paper in the journal BMJ Clinical Evidence.

Lupus nephritis has historically been treated with high doses of steroids and calcineurin inhibitors such as cyclosporine. But calcineurin inhibitors cause side effects that can limit their long-term use. High doses of cyclosporine can lead to arterial hypertension or hyperlipidemia, both of which are risk factors for cardiovascular disease—the primary cause of death for people with lupus nephritis.

“There’s been a long history of drugs failing on lupus nephritis,” Huizinga says. But over time, “we discovered these really interesting aspects of voclosporin that differentiate it from the legacy drugs that have been used in this disease.”

Voclosporin is an analog of the immunosuppressive drug cyclosporine in which a single amino acid has been modified. Voclosporin binds more effectively to calcineurin than cyclosporine does, making it effective at much lower doses. In Phase 2 and 3 clinical studies, voclosporin, given in combination with mycophenolate mofetil and steroids, was twice as effective as the current standard of care at achieving complete renal response—a measure of protein levels in the kidneys that is a key marker of recovery from lupus nephritis.

In addition, the tweak to the amino acid changes the way the drug is metabolized. It has fewer metabolites and so has fewer adverse effects and a more predictable pharmacokinetic profile across ethnicities, ages, sex, and clinical profiles, according to Aurinia. The compound seems to have no effect on lipid concentrations, thereby reducing the risk of hyperlipidemia.

More than 2,600 patients used voclosporin during its years in development, a number Huizinga is proud of. “Without their participation, and without organizations like the Lupus Foundation of America and the National Kidney Foundation, we would not have been able to do this,” he says. “Drugs are developed on the backs of relationships, and great drugs are developed on the backs of great relationships.”

Huizinga considers Aurinia’s cooperation with Lonza one of those great relationships. It goes back to 2004, when Lonza began to offer development services to Isotechnika and provided materials for clinical trials. Christian Dowdeswell, Lonza’s vice president of commercial development for small molecules, says the company is keen to support customers from an early stage through launch and commercialization of a product. “Taking the final step to enter into a commercial supply agreement was a natural progression of the way that we worked with Aurinia,” he says.

Isotechnika developed the single-enantiomer synthesis of voclosporin during a period of collaboration with Roche. Over the years, Lonza and the biotech firm were able to further refine the manufacturing process, making it as efficient and sustainable as possible, Dowdeswell says.

That included optimizing solvents and reagents for low toxicity profiles. Lonza developed a crystallization technique for voclosporin, a peptide, allowing the firm to move away from chromatography and the large amounts of associated solvent waste. The key was gaining a deep understanding of the impurity profile, Dowdeswell says, and the mechanics around controlling the crystallization procedure.

“There was a good deal of work in getting to a very scalable and controllable crystallization procedure, which, for a peptide, is no small feat,” Dowdeswell says. “But it’s our bread and butter to solve complex technical problems to make an API scalable.”

Voclosporin will be made in Visp at a dedicated plant that Lonza calls a monoplant. The Swiss firm opened its first monoplant, for Clovis Oncology’s cancer drug rucaparib, in 2018. Aurinia’s monoplant is scheduled to open in 2023; until then, demand will be met from inventory.

For Aurinia, a monoplant eliminates the inevitable wait for a manufacturing slot in a multipurpose plant. And Lonza can respond to changes in demand in weeks rather than months, Dowdeswell says. Max Donley, Aurinia’s executive vice president for operations and strategy, adds that monoplants allow manufacturing to be nimble, which is valuable for a new product that might encounter peaks and troughs in demand.

The privilege of a monoplant comes at a price, but neither Lonza nor Aurinia see this as significant in the grand scheme of things. “It’s a multivariable equation, for sure,” Donley says. “But, you know, as you think about the ability to move in a scalable way, without having to put the capital investment in place to build your own plant, it makes a lot of sense for a company in our position.”

Aurinia isn’t revealing its manufacturing targets for voclosporin, but it looks set to scale up. The company plans to file a marketing authorization application with the European Medicines Agency this year and has signed a licensing agreement with Japan’s Otsuka Pharmaceutical for the commercialization of voclosporin in Europe and beyond.

Huizinga says the drug will likely find applications beyond lupus nephritis. Already, a small study in Europe is exploring its effects on SARS-CoV-2-positive renal transplant patients. Meanwhile, Aurinia is working on treating kidney and autoimmune diseases with new compounds that could one day join the manufacturing line at the Visp monoplant.

Aurinia’s promising future is beginning to draw speculation over its continuing independence. In May, the UK newspaper the Times reported on “whispers” that AstraZeneca and GlaxoSmithKline are interested in a potential takeover. Donley says an acquisition is “not our strategy” but that an offer for the company would get “due consideration.” Come what may, the company’s priority, he says, is the patients whom voclosporin can help.

Vanessa Zainzinger is a freelance writer who covers the chemical industry.