Arguably, the foremost of the near-term competitors is F2G's olorofim. Olorofim is a member of the ortomide antifungal class targeting fungal dihydroorotate dehydrogenase (DHODH), which is involved in pyrimidine synthesis. Although not a broad-spectrum antifungal, it has broad microbiologic activity against several important invasive moulds. Available orally, olorofim has been awarded FDA Breakthrough Therapy Designation for the treatment of invasive fungal infections in patients with limited or no treatment options, including aspergillosis refractory or intolerant to currently available therapy, and infections due to Lomentospora prolificans, Scedosporium, and Scopulariopsis species as well as treatment of patients with coccidioidomycosis refractory to standard of care.

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In a strong endorsement of its commercial potential, F2G was able to attract the attention of Shionogi in a licensing agreement, which provided both funding for development and commercial rights in Europe and Asia. Signed in May 2022, F2G received $100m in upfront payments and could receive up to a further $380m in regulatory and commercial milestones as well as double-digit sales royalties.

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Olorofim was developed using the Limited Population Pathway for Antibacterial and Antifungal Drugs. US submission was based on the first 100 patients from a Phase 2b single-arm, open-label study (Study 32). Patients enrolled had limited treatment options for proven invasive fungal infections or probable invasive aspergillosis. Unfortunately for F2G and partner Shionogi, olorofim received a complete response letter from FDA in June 2023 following its application for approval with a proposed label for the treatment of invasive fungal infections in patients who have limited or no treatment options. At the time, F2G suggested that the resubmission would include data from the entirety of the Phase 2b study.

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Data from the Phase 2b study suggested that olorofim had an acceptable benefit-risk profile with overall success (the primary endpoint) of 28.7% at Day 42 and 27.2% at Day 84. More reassuringly, when considering stable disease as a clinically relevant endpoint, these numbers increased to 75.2% and 63.4%, respectively. Following the Phase 2b open-label study, a Phase 3 adjudicator-blinded trial (OASIS) comparing olorofim to AmBisome in patients with IA is ongoing, with a projected completion date of September 2025.

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Scynexis also looks to represent a powerful force in the anti-infectives field with its focus on the development of the "fungerp" class. The "fungerps" may share the same target as the echinocandins but targets a different binding site. First is Ibrexafungerp (SCY-078), which displays fungistatic activity against Aspergillus and fungicidal activity against Candida. Given a general lack of cross-resistance with the echinocandins and its availability as an oral presentation, there is the expectation that ibrexafungerp can be used as an oral step-down therapy to injectable echinocandins in the short term. However, a Phase 3 study (MARIO) with ibrexafungerp has been the subject of a clinical hold due to the risk of cross-contamination during manufacture and is expected to restart in H2 2024.

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Brexafemme (ibrexafungerp tablets) was approved for the treatment of recurrent vulvovaginal candidiasis (VVC and RVVC) and represented the first approval of a new antifungal class for 20 years and the first non-azole agent approved by the FDA for this indication. Endorsement of Brexafemme's potential was delivered by a partnership with GSK (amended in late 2023), with Scynexis receiving $90m in upfront payments as well as future performance-based milestone payments and tiered royalties in return for an exclusive license (ex-China).

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The antifungal pipeline at Scynexis now features its second-generation "fungerp" SCY-247. SCY-247 looks to have potent activity against a broad range of fungal infections, including multi-drug-resistant strains, including azole-resistant Candida and Aspergillus spp. If successful, SCY-247 could capitalise on the use of the echinocandins as first-line treatment options in invasive fungal infections caused by Candida and Aspergillus. SCY-247 has activity against resistant strains and appears more potent (greater bactericidal activity) than ibrexafungerp against resistant strains of C. auris and offers both IV and oral preparations.

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While the profile of SCY-247 looks promising, it is still in early development, with IND enabling studies currently ongoing with Phase 1 studies expected to start later in 2024.

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Despite the setback to olorofim, we are encouraged by the progress made to bring novel antifungals to market. The attraction of large pharma companies like GSK and Shionogi to in-license novel late-stage antifungal assets is reassuring and is a testament to the heightened awareness surrounding the increasing threat of fungal infections. It also demonstrates the advances in scientific endeavour, which has produced several novel antifungals after an apparent dearth for many decades. Bringing in fosmanogepix neatly transforms the long-term outlook for the antifungal franchise at Basilea.

 

BAL2062 is the first component of Basilea's defence

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BAL2062 is the first of a new class of siderophore-like hexapeptide antifungal agents. BAL2062 is differentiated by its novel mechanism of action that includes rapid fungicidal activity, with data generated to date suggesting activity against a range of difficult-to-treat fungal pathogens (including azole-resistant strains). The rapid reduction in fungal burden could be a highly attractive feature of BAL-2062, as well as a lack of cross-resistance to existing antifungal classes (such as the azoles).

 

BAL2062 originated at Astellas and is a naturally derived cyclic hexapeptide from the Malaysian leaf litter fungus. Its mechanism of action is based on the use by fungi (and other pathogens) of the siderophore ferrichrome. Fungi require Ferrichrome to scavenge for essential iron when levels are low. Significantly, it is transported in fungal cells by the Sit1 transporter, and fortunately, since human cells do not possess a Sit1 transporter, BAL2062 should have minimal toxicity.

 

Although the principal commercial target is likely to be invasive aspergillus infections, BAL2062 also has activity against other important fungal pathogens, including Candida glabrata and Fusarium solani.

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These remain early days for BAL2062, with Phase 1 clinical evaluation showing it to be safe and well tolerated. BAL2062 also benefits from QIDP and Fast Track designations for IA. Basilea intends to flesh out the profile of BAL2062 further with the intention of commencing Phase 2 trials in H1 2025.

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Ceftobiprole central to the antibacterial franchise

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Ceftobiprole may be a legacy 5th-generation cephalosporin, but it comes with an attractive label encompassing Staphylococcus aureus bacteraemia (SAB) as well as severe skin infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). Securing a relevant and commercially aligned partner has been a protracted process; however, the company intends to deliver the best deal for both ceftobiprole and Basilea, maximising the long-term commercial potential.

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Nevertheless, ceftobiprole provides a solid platform to help expand the company's anti-infective ambition. The addition of tonabacase and several OMPTA drug development programmes offers short- and long-term programmes. Successful prosecution of these programmes suggests that Basilea should ultimately possess a broad portfolio targeting many of the priority threats highlighted by agencies such as WHO and CDC.

 

Tonabacase – an alternative antibacterial approach

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Within the anti-infectives field, questions surrounding the commercial model for novel antibiotics have been the most concerning. This is perhaps unsurprising given that widespread usage needs to be curtailed if resistance is to be discouraged. As a result, antibiotic stewardship remains a key component of novel antibiotic development. There have been efforts to remove the link between financial reward and unit sales to encourage activity while maintaining the desire for antibiotic stewardship. We note, for example, the recent subscription plan launched in the UK whereby a fixed fee of up to £20m per drug would be paid irrespective of usage. Antibiotics that treat critical infections as deemed by the WHO would be prioritised.

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Another approach is to focus on areas where resistance is less of an issue and programmes where there is the potential to demonstrate superiority in clinical development compared to a more typical non-inferiority approach. The non-inferiority approach has likely led to a more conservative use of new antibiotics, as resistance tends to be more of a concern. The license and option agreement that Basilea has signed with iNtRON Biotechnology has brought in tonabacase – a clinical-stage antibacterial agent.

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Tonabacase is a recombinant endolysin and potentially represents a differentiated antibacterial approach. Endolysins, like tonabacase, are derived from bacteriophages which infect and kill bacteria. The history of the endolysins is worth revisiting. Arguably, phages represented one of the earliest approaches to treating bacterial infections. This approach fell out of favour as antibiotics, which offered a broader spectrum of activity against multiple bacterial infections, became the standard of care.

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However, endolysins have recently enjoyed renewed interest because of mounting resistance concerns regarding commonly used antibiotics. Endolysins have several important attributes, the most important of which we suspect is a lack of bacterial resistance mechanisms. Indeed, given the rise of multi-drug resistant bacteria and a lack of novel antibiotic classes, lysins and phage could enjoy a rekindling of interest. They also represent attractive antibacterial agents as they have activity against resistant bacteria like MRSA as well as biofilms and have demonstrated synergy with antibiotics.

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Given their mechanism of action, targeting peptidoglycan in bacterial cell walls, the endolysins generally are more effective against Gram-positive bacteria. However, we note encouraging activity against some Gram-negative species, often using modified lysins. Although we recognise the utility of endolysins as a stand-alone approach, we suspect that the potential to combine with existing antibiotic classes could be an attractive proposition for Basilea. In particular, we note encouraging historical data combining endolysin therapy with existing antibiotics targeting MRSA, suggesting greater efficacy and the potential for lower antibiotic dosing.

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Tonabacase was initially developed by iNtRON (SAL200) and out-licensed in 2018 to Roivant, with a new company, Lysovant, formed to develop and commercialise. As a sign of the programme's potential, the agreement could have been worth as much as $657.7m. As LSVT-1701, Lysovant undertook additional preclinical development, showing, for example, that tonabacase was active against a broad array of S. aureus isolates and coagulase-negative staphylococci.

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A combination of preclinical and limited clinical data suggests that tonabacase possesses attractive properties, including rapid bactericidal activity against various S. aureus strains, including MRSA and a low propensity to cause resistance. In addition to its potent anti-biofilm activity, it has been shown to work synergistically (in vitro and in vivo) with important anti-staphylococcal antibiotics such as daptomycin and vancomycin, which are routinely used where MRSA is suspected. As highlighted above, we suppose this is where Basilea's interest lies, noting, in particular, preclinical data demonstrating that tonabacase enhances the activity of standard of care antibiotics in a murine bacteraemia model. Since bacteraemia is the leading commercial prospect for ceftobiprole, the potential for tonabacase to enhance the already impressive results in this needy patient population is worthy of further investigation.

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Basilea will undertake further, as yet unspecified, preclinical evaluation as part of this license and option agreement. Assuming this is successfully completed, Basilea intends to progress tonabacase into Phase 2 development in 2025.

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Perhaps tempering some of our enthusiasm for the tonabacase programme has been the recent experience with exebacase and, in particular, the failure of the Phase 3 DISRUPT study evaluating exebacase along with standard of care antibiotics in the treatment of SAB and right-sided endocarditis. This was a well-designed study evaluating superiority (not non-inferiority) of a single IV dose alongside standard of care (SoC) antibiotics versus SoC antibiotics alone. Given the magnitude of the benefit seen in Phase 2 evaluation, the use of a superiority endpoint was justified. Importantly, however, additional analysis has provided some key learnings which hopefully will help Basilea as it seeks to define the potential of tonabacase in a similar patient population. Admittedly DISRUPT was conducted during the restrictions associated with the COVID-19 pandemic, which brings its own unique set of circumstances. However, other issues highlighted were apparent heterogeneity within the primary analysis population (sicker patients in the exebacase arm) as well as the use of a composite endpoint and a primary efficacy endpoint at Day 14 instead of a test-of-cure at Day 70. Furthermore, we note the profile of exebacase limited its administration to a once-daily dosing regimen, which may have limited its effect. Tonabacase, on the other hand, has a more favourable tolerability profile, facilitating a likely more effective multiple-dosing approach.

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Given the uncertainty associated with this approach (particularly post DISRUPT), we have not included any revenue contribution from tonabacase in our forecasts.

 

LptA platform – targeting Gram-negative infections

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The primary unmet need in bacterial infections has been problematic infections caused by Gram-negative bacteria. For Basilea, if the antibacterial franchise is to be extended beyond ceftobiprole, targeting Gram-negative infections represents the obvious target. Gram-negative infections are generally more challenging to treat than Gram-positive ones because the outer membrane blocks some antibiotic classes. Ceftobiprole, for example, may have an extended spectrum that includes some Gram-negative bacteria, but, in general, it would only be used where a broad-spectrum antibiotic is required. There is a clear desire, reflected in treatment guidelines, for a more tailored approach to treating infections where the causative agent can be ascertained.

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Therefore, resistance associated with Gram-negative infections is particularly concerning, with few treatment options and little progress. Such is the seriousness of AMR, that the WHO has published a list of priority pathogens, of which the majority are Gram-negative. The list is split into three priorities relating to their risk to human life. The highest-level Priority 1 pathogens are all Gram-negative and are deemed to pose a critical threat and comprise Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacteriaceae, where resistance has become a significant problem.

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Although these are still early days for this programme, and no target indications have been suggested, it is worth noting that bacteraemia, HAP, VAP, and urinary tract infections are often associated with Gram-negative infections.

 

The LptA programme has been focussed on disrupting the outer membrane of Gram-negative bacteria by targeting the LPS bridge. Given the importance of the outer membrane in preserving the integrity of Gram-negative bacteria and effectively blocking antibiotics from entering, targeting LPS production and its transport machinery has proven to be an attractive approach in antibiotic drug development. Nevertheless, apart from the polymyxins and colistin, which have significant limitations, direct inhibitors of LPS have been found wanting so far. Given the heightened risk of kidney damage associated with colistin and polymyxin B, they are usually only used as a rescue/ last resort treatment.

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Looking at the Spexis LptA programme, the lead candidates have demonstrated potent bactericidal activity against many important Gram-negative pathogens. Notably, the candidates have shown activity against colistin-resistant isolates.

The importance of the LptA programme has been reflected in the award of non-dilutive funding from CARB-X to aid development, which focuses on accelerating programmes targeting the WHO and CDC's priority list pathogens.

 

Ceftobiprole approaching US commercialisation

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US approval has been a long time coming for ceftobiprole. FDA approval has provided ceftobiprole with a broad label. Not only does the label include the key SAB indication and the large severe skin indication, but ceftobiprole is also approved for treating community-acquired bacterial pneumonia. Basilea may have flagged this broad label previously, bringing about a greater interest in forging a licensing agreement than previously thought. As a result, Basilea has not yet delivered a partner, although discussions/ negotiations are ongoing. No time must be wasted in securing a commercial partner and launching ceftobiprole in the US, given that the 10-year exclusivity clock is already ticking. However, it is important that the right partner on the right terms is secured and that partner's commercial objectives are aligned with Basilea's in maximising the commercial opportunity in the key US market.

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Previously, the company described a likely commercial scenario starting with SAB and subsequently involving other complications such as SAB-associated bone and joint infections, bacteraemia caused by ABSSSI, and other related indications.