It took nearly two decades from the start of tremelimumab’s first-in-human study until Astrazeneca saw the drug approved last week as Imjudo. This is undoubtedly a lesson in perseverance, but it does not in fact represent the longest development period of a drug from phase 1 to US approval.
That honour, at least looking at the past 25 years or so, belongs to Kyowa Kirin’s Nourianz, which got an FDA green light in 2019 as an add-on in Parkinson’s disease, a culmination of over 20 years of trials in more than 4,000 patients. An Evaluate Vantage analysis identifies several other drugs that, like Imjudo, offer important lessons at a time when failing early and failing fast are industry bywords.
Of course, for tremelimumab’s originator, Pfizer, the project effectively did fail. As long ago as 2008 Vantage was writing about the drug, then known as CP-675,206 or ticilimumab, being one of that year’s big launches; however, after seeing insufficient monotherapy activity Pfizer divested rights to Astra in 2011.
And Astra almost discontinued it too, deprioritising the molecule after seeing it yield lacklustre results in study after study. It was only the surprising 2021 hit in the first-line liver cancer trial Himalaya, in combination with Imfinzi and partly put down to a novel dosing regimen, that showed tremelimumab to be active, and the rest is history.
Vantage’s analysis makes Imjudo’s development period the fourth-longest among a cohort of recent US drug approvals: nearly 231 months from first-in-human trial to FDA thumbs up. After Bristol Myers Squibb’s Opdivo Imjudo is the second anti-CTLA-4 MAb to get US approval, and a remarkable 11 years, six months and 29 days separate these two drugs’ green lights.
| Pharma’s longest developments: selected products | ||||
|---|---|---|---|---|
| Product | Company | First US approval | Development time (mths)* | NPV+PV ($m)** |
| Nourianz/Nouriast | Kyowa Kirin | Aug 2019 | 272 | 770 |
| Livtencity | Takeda | Nov 2021 | 265 | 798 |
| Zokinvy | Eiger Biopharmaceuticals | Nov 2020 | 258 | 96 |
| Imjudo | Astrazeneca | Oct 2022 | 231 | 293 |
| Jynneos | Bavarian Nordic | Sep 2019 | 222 | 442 |
| Cinqair | Teva | Mar 2016 | 210 | 250 |
| Tlando | Halozyme | Mar 2022 | 199 | 324 |
| Koselugo | Astrazeneca | Apr 2020 | 190 | 883 |
| Rydapt | Novartis | Mar 2017 | 183 | 1,484 |
| Afrezza | Mannkind | Jun 2014 | 179 | 243 |
| Note: *from first-in-human study start (or date received, if unknown), according to company info, scientific publications or clinicaltrials.gov; **measure of total value of cashflow over product’s lifetime. Source: Evaluate Pharma. |
One of the most important considerations for any company wondering whether to press on in such circumstances is the ticking clock on patent expiry. Despite this, three drugs have beaten Imjudo’s drawn-out development history: Nourianz/Nouriast, Takeda’s Livtencity and Eiger’s Zokinvy.
The first of those is notable for entering the clinic all the way back in 1996, and having first been knocked back in 2008, when the FDA considered its modest motor benefit insufficient to back approval. Kyowa then undertook additional trials in Japan – where the drug got a regulatory nod in 2013 – and finally the US regulator relented three years ago.
Though this ultimately represented a win, whether Kyowa will ever recoup the cost of a 4,000-plus patient clinical programme is uncertain; Nourianz’s lifetime profits will amount to just $770m, Evaluate Pharma calculates.
Though Livtencity and Zokinvy were studied in fewer patients, their respective 2021 and 2020 approvals, for post-transplant CMV infection and Hutchinson-Gilford progeria syndrome, raise similar considerations. Interestingly, before Zokinvy (AKA SCH 66336) ever showed potential in a rare disease Schering-Plough was studying it for cancer.
Similarly, Mannkind’s controversial inhaled insulin Afrezza is only expected to play a minor role in treating diabetes, having been launched in 2014 at the cost of some $2bn over the best part of two decades.
Those wondering whether it is sometimes worth cutting your losses early might also consider two industry projects that do not appear on the list by virtue of not having yet been US-approved. Mesoblast’s Ryoncil and Basilea’s Zevtera have endured notable setbacks, despite which their developers still see a path forward.
If approved in 2022/23, as some analysts hope, these will respectively have spent 18 and 14 years in the clinic.
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