From The Editor | October 30, 2024

How Cidara Got Its Molecule Back

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By Matthew Pillar, Editor, Bioprocess Online

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Way back in November 2021, Cidara Therapeutics entered into a collaboration agreement with Janssen Pharmaceuticals, Inc., one of the Janssen Pharmaceutical Companies of J&J, to advance the development of Cidara’s lead drug-Fc conjugate (DFC), a compound called CD388 that was pre-clinical at the time. CD388 is a long-acting antiviral drug that combines an approved virus-targeting small molecule with the Fc portion of a human antibody, and the intention of the partnership was to crack the decades-long challenge of a universal flu preventative.

Cidara took an upfront payment of $27 million from J&J to advance the drug, with the potential to earn $753 million more in R&D funding and milestone payments. J&J reimbursed Cidara for all development costs under the agreement.

In a dramatic turn of events that makes for some great storytelling, that asset is now squarely back in Cidara’s hands and moving forward with an aggressive phase 2b study.

Act 1: J&J Exits Infectious Disease

Jeffrey Stein, Ph.D., President & CEO, Cidara
Cidara President & CEO Jeff Stein, Ph.D. tells me that under its agreement with Janssen, Cidara was responsible for executing on the clinical development of CD388 up through phase 2a. “We conducted two phase 1 studies and a phase 2a study that read out last spring, and, based on the strength of results of those three clinical studies, Janssen decided to exercise its opt-in rights to take over late-stage clinical development of CD388,” says Stein. “Basically, we’d be handing them the keys to the car, and they would drive it forward into phases 2b and 3.”

However, immediately after that decision, J&J made a different and much broader strategic decision – to exit infectious disease development and to divest its clinical portfolio of programs . Those cuts included its work on the then phase 2a asset CD388.

As part of the divestiture of its infectious disease portfolio, Janssen was looking to recoup investment as well as benefit from future value from its portfolio. That’s exactly what it did with its E. coli vaccine and hepatitis B programs, which it divested to Sanofi and GSK, respectively. CD388, its third-most advanced infectious disease program, appeared to be staring down a similar fate.

Late in the fall of 2023, Stein and his team at Cidara entertained the possibility of winning the molecule back. That would require a gargantuan effort.

“We invented CD388, held the IND, and controlled the drug supply. We felt as though we were the only company that had any chance of starting a phase 2b study in 2024,” says Stein.

Acts 2, 3, & 4: Shuffling The Deck To Support A Reacquired Asset

Cidara wasn’t the only bidder at the CD388 auction. To get the molecule back, the first thing Cidara needed was money. “That's when RA Capital Management serendipitously approached us,” says Stein. RA was familiar with Cidara’s Cloudbreak platform, and had supported the company during its crossover round and IPO in 2015. Bain Capital Life Sciences, BVF Partners, and Canaan Partners joined RA, and soon the company had raised $240 million to support a Phase 2b study. “We found ourselves with the resources to compete with Big Pharma and another venture syndicate that had been vying for the molecule, and we had the unique net present value advantage of being able to start a phase 2b study sooner,” he says.

Securing the funds to compete for, and ultimately win back, CD388 was just the first of many challenges Cidara accepted to continue the molecule’s clinical momentum. “With the financial backing to compete in hand, we still had to have a convincing proposal to Janssen to demonstrate why we were the best company to move the compound forward,” says Stein.

Cidara also had to reshuffle its business and development priorities. A little over a year ago, when all these parts were in motion, the company had an approved antifungal called rezafungin (marketed as Rezzayo), which it had advanced from preclinical stage to approval in the US and EU. Cidara had out-licensed the commercial rights to rezafungin to Melinta Therapeutics in the U.S. and Mundipharma outside the US and Japan. “It was very clear to us that we could not get a CD388 deal secured with Janssen, much less get money committed from our capital partners, unless we divested our interests in rezafungin,” says Stein. “We needed to demonstrate that all of our capital and human resources would be focused on the CD388 program.”

Thus, Stein and his team found itself in the throes of three distinct, yet inextricably linked high-stakes negotiations late last year; one with Janssen, one with its capital partners, and one with Mundipharma, to which Cidara ultimately divested rezafungin. Its timing on each needed to be impeccable.

“The capital raise and Janssen deals were dependent on getting the divestiture of rezafungin done,” says Stein, “But as a public company, we couldn’t divest rezafungin too far ahead of the capital raise and Janssen deals, because the market wouldn’t know those deals were coming. How would the market reconcile us divesting a product we were earning milestone payments and royalties on?”

Through a lot of hard work and a little bit of luck, those stars aligned. All three deals were announced on the same April 2024 day.

Interlude: Why Move Mountains For CD388?

What moved Stein to move mountains to keep CD388 on an even keel? The same thing that moved Janssen/J&J to snap it up in the first place, before what Stein characterized as a “their loss but our gain” decision to exit the infectious disease space.

“Our invention of CD388 represents a new approach to universal prevention of Influenza. A single dose of a long-acting drug that protects people from all strains of influenza,” says Stein. He’s steadfast in his declaration that a ‘universal flu vaccine’ will never exist. “Even the most advanced vaccines require an immune response to an antigen,” he explains. That’s a tall order, particularly in influenza, where seasonal strains and mutations evade vaccination efforts. “Your typical seasonal flu vaccine’s protective efficacy is about 40% in healthy recipients, and that diminishes by 8% to 10% per month. There’s a big swath of the populace who are immunocompromised or otherwise predisposed to have vaccine response as low as 5%,” says Stein. It’s no wonder fewer than 45% of U.S. adults opt in to an annual flu vaccine. That number has been dropping by multiple percentage points annually since prior to the COVID pandemic.

CD388 is not a vaccine. It’s a completely new modality, comprised of the Fc Domain of a human antibody, conjugated to multiple copies of a potent small molecule inhibitor called zanamivir.

Zanamivir is an approved drug for the prevention and treatment of influenza, marketed by GSK as Relenza in an inhaled dosage form. “Relenza should be a great flu drug,” says Stein, “but it’s not, because it has poor drug properties.” That’s in part because, while it’s ultra-potent, it can only be administered in an inhaled dosage form – not as a subcutaneous or intramuscular injection. He says Cidara’s drug-Fc conjugate approach boosts zanamivir to its full potential for multiple reasons:

  • The Fc portion of the antibody used in the conjugate can carry multiple copies of zanamivir, thus enabling interaction with multiple viral particles, amplifying its potency,
  • Because zanamivir is conjugated to the Fc portion of a human antibody, it can be injected intramuscularly or subcutaneously,
  • By virtue of conjugation to a human antibody fragment, the drug cannot penetrate human cells, mitigating drug interactions and off-target toxicities.

Act 5: Manufacturing Novel Conjugates: Easier Than ADCs

Further extoling the virtues of its novel molecule in comparison to standard approaches to influenza therapeutics, Stein says CD388 can be manufactured at a cost of goods that’s closer to a small molecule than that of a mAb. “Monoclonal antibodies are challenging,” he says. “They are large molecules with relatively poor tissue distribution which requires high doses, especially for indications like influenza, which requires distribution to the respiratory tract. They are also relatively expensive to develop and manufacture,” he says. Those attributes are inconsistent with the profile needed for an influenza preventative.

Small molecules alone, says Stein, also have their liabilities. While less expensive to manufacture, there are a limited number of them that address influenza, “and those that do require daily administration and demonstrate rapid resistance.”

One of Janssen’s early requirements of its initial collaboration with Cidara was that the cost of goods incurred by the drug’s manufacture had to be no greater than 15% of the selling costs. CD388, according to Stein, falls well within that scope.

While it’s easy to consider Cidara’s drug-Fc conjugate approach as a form of an ADC, Stein says there’s a stark contrast between how ADCs and Fc conjugates are manufactured. That contrast begins and ends with how they work. While most ADCs makes full use of a full antibody – its variable domains targeting an overexpressing epitope on cancer cells, for example, and its Fc domain carrying the toxic payload into those cells – Fc conjugates are simply Fc fragments featuring covalently-attached small molecules that are delivered to the virus to inhibit neuraminidase, an enzyme that’s essential for the virus to break out of the infected cell.

“ADCs represent a very complicated and expensive manufacturing process,” says Stein. “You’re making a monoclonal antibody, which is cumbersome and expensive in itself. Then you have a toxic moiety that typically requires separate manufacturing facilities. It’s a multi-step, multi-location manufacturing process, which contributes to the high cost of ADCs.”

Cidara, by contrast, doesn’t have to make monoclonal antibodies. It’s synthesizing CHO cells to express just the Fc portion of antibodies. Nor does the company need to manufacture toxic payloads that are then conjugated in a wholly separate facility. All processes can be executed under the same roof.

Act 6: International Clinical Trial Progresses

On the heels of its reacquisition of CD388, Cidara initiated its international phase 2b clinical study in September 2024. The trial, designed to study the safety and efficacy of the molecule as a pre-exposure prophylaxis of influenza during the current flu season, intends to enroll and dose 5,000 unvaccinated subjects in the U.S. and U.K. by the beginning of December. Three different single-doses (plus placebo) will be tested in those patients, and they will be monitored throughout the flu season.

The suspenseful drama that follows CD388 is far from over. Should its phase 2b trial see success (and perhaps, even before), Cidara will have some newfound challenges to address, not the least of which will be the onshoring of its CD388 manufacturing facilities. That effort is currently under contract with WuXi, a lead character in another big-budget biotech drama that’s still being written on the Biosecure Act. We’ll visit with Stein again when the Flu Season ’25 end credits are rolling.