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Biotech firms on the shoulders of giants

Pharmaceutical services companies like Seqens, Lonza, and Evonik make many of the biotech industry’s small-molecule drugs

June 27, 2021 | A version of this story appeared in Volume 99, Issue 24
An illustration of a person in a lab coat, goggles, and gloves standing on the shoulder of a much larger person, who is also wearing a lab coat, goggles, and gloves along with a mask. The person on the shoulder gestures with his gloved hand to a structure floating in the air. The background contains pill bottles and industrial equipment.

Credit: Mike Reddy

The drug industry’s biggest players are massive. Pfizer’s sales last year were almost $42 billion. Johnson & Johnson’s were $83 billion. These companies have deep internal resources, and they closely direct any tasks they farm out to smaller firms.

But these days, many new drugs come from much smaller biotechnology firms that don’t have nearly the same resources. So when it’s time to manufacture the molecules at the heart of their drugs, biotechs often turn to outsourcing companies for help.

Increasingly, these outsourcing companies are big—much bigger than the biotech firms they are aiding. But that difference doesn’t bother many biotech executives, who appreciate the helping hand of a large, experienced partner. Read on for three stories of small biotechs that turned to large outsourcing partners to manufacture their small-molecule drugs.


Case Study 1

Synthesizing a natural product

Mithra chooses Seqens to scale up manufacturing of an estrogen found in nature

by Michael McCoy


Credit: Seqens
Seqens's 128-year-old site in Villeneuve-la-Garenne, France, continues to get new investment.

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.”

There was a need to find a different provider to get a better yield.
Jean-Manuel Fontaine, vice president of external and scientific affairs, Mithra Pharmaceuticals

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.”


Case Study 2

A long collaboration arrives at the production stage

Aurinia will use a dedicated Lonza plant to produce its new lupus nephritis drug

by Vanessa Zainzinger, special to C&EN


Credit: Lonza
Having its own facility at Lonza's Visp, Switzerland, site means Aurinia Pharmaceuticals won't have to wait for space at Lonza's multipurpose complex, a part of which is shown here.

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.

Great drugs are developed on the backs of great relationships.
Robert Huizinga, executive vice president of research, Aurinia Pharmaceuticals

“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.


Case Study 3

A small firm checks in at a big partner’s complex

Cassava picks Evonik to make the experimental Alzheimer’s disease treatment simufilam for Phase 3 clinical trials

by Rick Mullin


Credit: Evonik Industries
Evonik Industries acquired its Tippecanoe site in Lafayette, Indiana, from Eli Lilly and Company in 2009.

The controversial approval of Biogen’s Aduhelm earlier this month spotlights the challenges for big companies developing antibody treatments for Alzheimer’s disease. The US Food and Drug Administration signed off on the drug, but many neurologists were unimpressed, if not frustrated, with the approval, viewing the antibody’s impact as marginal at best and the FDA’s vetting as substandard.

Recent results from a Phase 2 clinical trial of a small-molecule Alzheimer’s disease treatment developed by the tiny biotech firm Cassava Sciences, however, suggest a new approach to halting the progress of the seemingly intractable neurodegenerative disease.

“Clinical data around our compound is very promising,” says Remi Barbier, CEO of Austin, Texas–based Cassava, which Barbier founded as Pain Therapeutics in 1998. “If the data continues to replicate, then we are looking at a monster, monster commercial manufacturing opportunity.”

Simufilam at a glance

Discovered: 2010 by Cassava Sciences scientists

Indication: Alzheimer’s disease

Innovation: Restores normal shape and function of altered filamin A, a scaffolding protein

Status: Phase 3 clinical trial planned for second half of 2021

Something of a David among pharma Goliaths, Cassava has signed with a giant among contract development and manufacturing organizations (CDMOs)—Evonik Industries—for Phase 3 and potentially commercial manufacturing of simufilam, the active pharmaceutical ingredient (API) in its drug candidate. Still in its early stages, the project may seem lost on Evonik’s sprawling Tippecanoe campus in Lafayette, Indiana, a former Eli Lilly and Company factory. But it could take up sizable real estate at Tippecanoe if Phase 2 results carry over to Phase 3 and the drug is approved.

And Barbier is optimistic that simufilam will score that breakthrough.

Most drugs being developed for Alzheimer’s disease are large molecules that target the buildup of amyloid-β plaque or tau fibrils in the brain. While these drugs reduce plaque buildup, there is no conclusive evidence of improved cognition as a result. Simufilam, on the other hand, aims to neutralize the ill effects of neuroinflammation and neurodegeneration attributed to plaque buildup.

“It works by binding with superhigh affinity—with femtomolar affinity—to target a protein called altered filamin A,” Barbier says. “It’s a scaffolding protein, one of several scaffolding proteins that physically hold you up.”

People with Alzheimer’s disease have an altered shape of filamin A. Simufilam binds to receptors on the protein, restoring its shape and function. “And when you restore the shape and function of filamin A,” Barbier says, “you stop many of the downstream pathologies associated with Alzheimer’s disease.” Cassava holds seven patents covering a range of filamin-binding molecules. It hasn’t disclosed which one it is developing as simufilam.

The compound demonstrated positive cognitive effects with no safety issues in Phase 2b studies that were completed last year. In a 6-month interim analysis of a separate, ongoing study, simufilam improved cognition in people with Alzheimer’s disease, the firm says.

Looking for a contract manufacturer to produce simufilam for Phase 3 trials, Cassava came across Evonik serendipitously, according to Barbier. “One of our guys here worked with Evonik previously. He had a good experience, so we put them on the short list,” he says. The German firm came out “head and shoulders” above the rest on that list in subsequent due diligence, Barbier says.

If the data continues to replicate, then we are looking at a monster, monster commercial manufacturing opportunity.
Remi Barbier, CEO, Cassava Sciences

Barbier says he had learned to approach large contract manufacturers with caution. “If you get people from a big company that are rigid and tell you, ‘This is how we have always done things,’ you should pretty much run away.” Evonik, he says, listened to Cassava’s requirements and reviewed earlier simufilam development work so it could understand unique aspects of the chemistry without imposing a template approach.

”We found a team that rolls up its sleeves,” Barbier says. “They don’t start with ‘The problem is . . .’ and then launch into 30 different problems. We know what the problems are. What we’re looking for are solutions.”

Cassava liked Evonik well enough not to pursue a single-source deal with another service firm that offered to provide both API and finished-dose drug production. Cassava, according to Michael Zamloot, senior vice president of technical operations, decided to choose the best fit at each stage rather than opt for the theoretical efficiency of working with a single service company.

“We have a selection process that is multivariable,” he says. “We consider the facilities, the scientific staff, the track record of the company, their experience with regulators.” A good working relationship with Evonik emerged, Zamloot says.

Working with a small company is not a new experience for Evonik, says Eric Neuffer, the firm’s senior director of CDMO sales. “We actually enjoy working with smaller companies because they are quick to make decisions,” he says. And the Cassava project has proceeded without the typical holdups.

Those holdups can include issues with the handling, isolation, and stability of APIs or unusual solvent requirements, Neuffer says. But Cassava presented a “very well-developed package.”

Neuffer says capacity considerations were essential to striking a deal. “Part of the reason they came to us is that they saw we had the right-size equipment,” he says. “They were in clinical Phase 2 heading into Phase 3. They needed batches less than 100 kilos to supply their clinicals, with the capability to get into metric tons. So we are operating this process with anything from 500 gallons to up to 4,000 gallons.”

Cassava has had only a virtual look at the vessels at its disposal because all meetings between the companies have been via phone and videoconference since they started working together early last year. “Just recently,” Neuffer says, “we gave them a video introducing them to the people involved with the project. It then went into each of the facilities and showed what was going on in the reactor.”

All contracts present challenges, says Paul Nichols, director of research, development, and innovation for Evonik’s health-care division. But not every project brings the same level of excitement. “When you talk about the possibility of being involved in bringing an Alzheimer’s drug forward, this is something that motivates people at our site,” Nichols says.

Bernard Munos, a senior fellow at FasterCures, a center at the Milken Institute, sees some justification for excitement about Cassava. “They offer what patients, clinicians, and investors have been clamoring for in the Alzheimer’s space but have never received,” he says in an email, commending Cassava on a comprehensive hypothesis that integrates suspected disease triggers from prior research including amyloid-β toxicity.

“This is far more elaborate than the rationales that support the β-amyloid or tau hypotheses,” Munos says. Cassava needs to do more to develop a companion diagnostic, says Munos. But he is impressed with the trial data to date. “No retrospective analyses; no anecdotal evidence; no trial protocol modification in midcourse; no ‘novel’ composite end points; none of the tricks that companies resort to when they cannot support their hypothesis with well-run, controlled trials.”

Simufilam enters Phase 3 with some momentum, though Phase 3 has been unkind to other potential Alzheimer’s therapies. In any case, Evonik says it is ready to scale up. And the partners are looking toward an important near-term milestone—meeting in person at the Tippecanoe site as COVID-19 restrictions are lifted. “Hopefully we can have them out to our site this summer,” Neuffer says.


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