Olorofim: New Antifungal Drug

Highlights

UK-based F2G is developing the experimental antifungal drug olorofim.

Olorofim is the first representative of a new class of antifungal drugs called orotomides.

The primary therapeutic target of olorofim is invasive aspergillosis, one of the most severe and difficult to treat forms of systemic fungal infections faced by individuals with weakened immune systems and which can prove fatal. Olorofim is in high demand due to the increasing prevalence of microorganisms that cannot be eradicated by standard drugs due to drug resistance.

In mid-May 2022, Shionogi & Co. entered into a license agreement with Ef-tu-ji for the clinical development and marketing of olorofim in Europe and Asia. The Japanese pharmaceutical giant paid $100 million up front and promised to give up to $380 million more as regulatory and commercial milestones are passed, plus double-digit royalties from sales of the finished drug.

When olorofim goes on sale, it will probably be called Olarivil or Orotamil. It is possible that the brand name will be Nufimgi or Fymforzo.

Shionogi & Co. is known for its powerful anti-infective developments. For example, the anti-influenza drug Xofluza (baloxavir marboxil) can be taken just once to speed up recovery or to protect against seasonal flu. Fetroja/Fetcroja, a “Trojan horse” antibiotic, easily handles drug-resistant aerobic gram-negative pathogens. Finally, Xocova (ensitrelvir) treats COVID-19 infection just as effectively as the strong Paxlovid (nirmatrelvir + ritonavir) by Pfizer.

 

What is Invasive Aspergillosis

Invasive aspergillosis is an infection with opportunistic mold of the genus Aspergillus, which are endemic worldwide in soil and decomposing organics. [1] [2] [3] [4]

Aspergillus fumigatus is the most common infectious agent (57% of cases) causing invasive aspergillosis. Infection can occur with other Aspergillus species, including A. flavus (12%), A. niger (12%), and A. terreus (10%). [5]

People breathe in Aspergillus spores daily, but invasive aspergillosis usually develops in immunocompromised individuals. Relevant immune deficits can be caused by hematologic malignancy (over half of invasive aspergillosis cases), chronic granulomatous disease, immunosuppressive treatment of graft-versus-host disease, advanced AIDS.

Additional risk factors include acquired immune defects (e.g., during chemotherapy or treatment with immunomodulators), congenital immune defects (e.g., polymorphisms in pentraxin 3 (PTX3) or toll-like receptor 4 [TLR4]).

The main route of infection is airborne contact with Aspergillus spores (conidia) in the environment (inhaling them). Other routes of infection include ingestion of contaminated food or water, direct inoculation through skin lesions (e.g., in burn patients). Human-to-human transmission does not occur.

In immunocompetent individuals (with a healthy and active immune system), the intact sinorespiratory epithelium and innate and adaptive immunity clear the respiratory tree of Aspergillus spores before they germinate. And so the incidence of invasive aspergillosis is extremely low, at approximately 2.4 cases per 100,000. [6]

In immunocompromised people (those with impaired or suppressed immune systems), Aspergillus spores germinate to form invasive hyphae, long branching structures collectively called mycelia. The hyphae produce proteases necessary to damage tissue and modulate the immune response. The incidence of invasive aspergillosis in at-risk groups is quite high, at approximately 10%. [7] [8]

Invasive aspergillosis most commonly affects the sinopulmonary tract, manifesting nonspecifically as pneumonia, tracheobronchitis, or sinusitis.

Complications of invasive aspergillosis include hemoptysis, vascular invasion, and disseminated infection.

Mortality in invasive aspergillosis exceeds 80% in high-risk patients, such as recipients of allogeneic hematopoietic stem cell transplants.

Due to the invasive potential of molds of the genus Aspergillus, rapid diagnosis and initiation of antifungal therapy are essential.

Treatment of invasive aspergillosis involves the administration of antifungal medications for a minimum of 6–12 weeks. The first-line treatment is voriconazole administered first intravenously and then orally. An alternative first-line treatment is intravenous liposomal amphotericin (amphotericin) followed by oral voriconazole. Salvage therapy (for first-line failure) turns to either intravenous caspofungin (or micafungin) followed by oral voriconazole (or itraconazole) or oral posaconazole.

Prevention of invasive aspergillosis is fair for high-risk patients: for example, recipients of hematopoietic stem cell transplants with prolonged neutropenia.

 

Mechanism of Action of Olorofim

Olorofim (F901318) is the first representative of orotomides, a new class of antifungal drugs.

Targeted at fungal nucleic acid metabolism, olorofim is a direct competitive highly selective inhibitor of fungal dihydroorotate dehydrogenase (DHODH), a key enzyme in the de novo pyrimidine biosynthesis pathway. Interruption of pyrimidine synthesis disrupts nucleic acid production, which leads to a halt in hyphae outgrowth. [1]

Olorofim is unique among other antimycotic drugs in that it has no activity against Candida spp. and Cryptococcus spp. [2]

Olorofim is characterized by potent activity against Aspergillus spp. wild-type and azole resistant, some other highly resistant hyaline molds, Coccidioides spp. For example, the antifungal activity of olorofim, studied on a hundred isolates of Aspergillus spp. that are azolo resistant due to point mutations or unknown mechanisms, showed that its minimum inhibitory concentration (MIC) was 8–64 times lower than that of voriconazole and amphotericin B. [3]

In vitro, olorofim is excellent against Scedosporium spp. and Lomentospora prolificans, [4] [5] [6] works against some Fusarium spp., [7] and has no activity against Mucorales and Exophiala dermatitidis. [1] [8]

Olorofim, developed in oral and intravenous formulations, initially has a fungistatic effect on Aspergillus isolates but with prolonged exposure it becomes fungicidal. [9] [10] [11]

 

Olorofim: Clinical Development

Olorofim is in the FORMULA-OLS (NCT03583164) phase 2b (non-randomized, open-label, multicenter, international) clinical trial testing its effectiveness in the treatment of invasive fungal infections caused by Aspergillus spp., Scedosporium spp., Lomentospora prolificans and other fungal microorganisms resistant to therapy with standard drugs. The study is conducted among patients (n=200) aged 16 years and older for whom there are no suitable treatment alternatives (refractory disease, treatment resistance, intolerance to existing medications).

How oral olorofim handles the treatment of aspergillosis, scedosporiosis, lomentosporiosis, and other rare infections caused by azole resistant molds is evaluated by response criteria according to a combination of clinical, mycological, and radiological results at day 42.

A phase 3 (randomized, double-blind, active-controlled, multicenter) OASIS (NCT05101187) pivotal clinical trial is scheduled for launch, which will compare the therapeutic efficacy of oral olorofim with the intravenous AmBisome (liposomal amphotericin B) by Gilead Sciences among adult patients (n=225) with invasive aspergillosis.

 

Olorofim: Market Outlook

Invasive fungal diseases caused by treatment-resistant yeasts and molds pose a serious threat to public health due to several factors: the growth of the population of immunosuppressed carriers, increased drug resistance to antifungals, improved laboratory diagnosis. Significant morbidity and mortality (in some cases up to 90%) associated with these pathogens indicate the urgent need to develop new effective and safe antimycotic drugs.

Four major classes of antifungal drugs are now available for the prevention and treatment of invasive fungal diseases: polyenes (e.g., nystatin, amphotericin B), azoles (e.g., ketoconazole, clotrimazole, fluconazole, voriconazole), allylamines (e.g., butenafine, terbinafine) and echinocandins (e.g., caspofungin, micafungin). There are also single agents that do not belong to these classes: e.g., flucytosine, griseofulvin, tolnaftate. The use of antifungals is often difficult because of toxicity, drug interactions, and lack of oral form.

Only recently, in June 2021, Brexafemme (ibrexafungerp) appeared, which discovered the triterpenoid class. Ibrexafungerp, developed by Scynexis for the treatment of vulvovaginal candidiasis (vaginal yeast infection), is the first representative of a new class of antifungals in more than 20 years.

In general, antimycotics belonging to new classes of drug compounds appear very rarely, as in the case of antibiotics. This is why olorofim has quite decent prospects. With the global market for antifungals estimated at $13–15 billion in 2021, there is definitely a place for olorofim.

In addition to invasive aspergillosis, olorofim is also suitable for the treatment of other hard-to-treat fungal infections including rare ones such as scedosporiosis, lomentosporiosis, coccidioidomycosis (Valley fever), talaromycosis, fusariosis, paecilomycosis, acremoniosis, eumycetoma (Madura foot).

F2G already has data from the first hundred patients from FORMULA-OLS (NCT03583164) phase 2b. It remains to wait for the results on the second hundred patients (they will be disclosed in the fall of 2022) to expand the safety data set. And then it is time to apply the New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA). This is possible due to the fact that the clinical trial was not conducted as a non-inferiority trial (the usual one for anti-infective drugs), but under the limited population pathway for antibacterial and antifungal drugs (LPAD pathway) used for life-threatening infections that affect small groups of patients and cannot be adequately treated with the available drugs. This is why FORMULA-OLS uses a historical control and an open-label design.

For approval of olorofim in other countries, it will have to wait for OASIS (NCT05101187) phase 3 readiness, which has already begun in Europe.

 

Extras

Spectrum of activity of F901318, the first agent from the new orotomide class of antifungals. Interscience Conference of Antimicrobial Agents and Chemotherapy (ICAAC). September 2015. [PDF]

Activity of F901318 against azole-resistant and difficult-to-treat Aspergillus species. European Congress of Clinical Microbiology and Infectious Diseases (ECCMID). April 2016. [PDF]

The novel orotomide F901318 demonstrates potent in vitro antifungal activity against Lomentospora and Scedosporium species. ECCMID. April 2016. [PDF]

In vitro susceptibility testing of the novel orotomide antifungal agent F901318 against Australian Scedosporium and Lomentospora pathogens. ECCMID. April 2017. [PDF]

Antifungal susceptibility profiles of olorofim [formerly F901318), and currently available systemic antifungals against mould and yeast phases of Talaromyces marneffei. ECCMID. April 2020. [PDF]

Molecular characterisation of Fusarium oxysporum species complex isolates from the United States and susceptibility profile of the investigational antifungal olorofim. ECCMID. April 2020. [PDF]

In vitro susceptibility of olorofim against 1,682 clinical Aspergillus isolates. Trends in Medical Mycology (TIMM). October 2019. [PDF]

Olorofim is potent against M. mycetomatis — most common eumycetoma causative agent. TIMM. October 2019. [PDF]

Successful use of the novel antifungal olorofim in the treatment of disseminated coccidioidomycosis. ECCMID. April 2020. [PDF]

A case of Lomentospora prolificans (Lo Pro) treated with the novel antifungal olorofim. ECCMID. April 2020. [PDF]

Olorofim for a case of severe disseminated Lomentospora prolificans infection. ECCMID. April 2020. [PDF]

Resistance profiling of Aspergillus fumigatus to olorofim indicates absence of intrinsic resistance and unveils the molecular mechanisms of acquired olorofim resistance. Emerg Microbes Infect. 2022 Dec;11(1):703-714. [source]