Perhaps Savara suffers from being in the unglamorous sector that is lung disease. Or maybe the company’s stealthy entrance onto the public markets means that it has flown under many investors’ radars. But the group finds itself on the verge of reporting pivotal results with its lead project, Molgradex, with a market cap of under $340m.
The company’s chief executive, Rob Neville, believes that data from the Impala trial in autoimmune pulmonary alveolar proteinosis (aPAP), due in June, could spur interest in the company. Indeed, he tells Vantage that Savara hopes to follow in the footsteps of another lung disease player, Insmed, which is making a good fist of marketing Arikayce alone, and is now worth a cool $2.5bn.
|NPV as % market cap||95%|
|Event||Data from phase III Impala trial|
However, to reach these heights Savara will need to get approval for Molgradex, an inhaled formulation of the endogenous immune system stimulant GM-CSF. It will also have to execute a successful launch, something that has eluded many a small company.
Mr Neville is confident that Savara can sell the drug in the US and key European countries itself with a sales force of around 30 people. But if Molgradex reaches the market it will go up against an off-label, do-it-yourself version of inhaled GM-CSF that will presumably be much cheaper.
aPAP is a rare disorder characterised by a build-up of surfactant in the lungs, which leads to difficulty breathing and predisposes patients to lung infections. The current standard of care is whole lung lavage, a procedure to “wash” the excess surfactant out of the lungs that is carried out under general anaesthetic. Severely affected patients can need regular lavages every few months, according to Mr Neville.
The disorder is caused by an autoimmune response to GM-CSF, which has an important role in the development of the lung macrophages that clear surfactant. By replacing GM-CSF Molgradex is designed to reactivate macrophages and in turn decrease surfactant levels.
Mr Neville believes that Savara will benefit from the fact that this mechanism is well validated, but this could also be the company’s downfall. Some doctors have already created their own workaround by taking an injectable formulation of GM-CSF, Leukine, putting it into a nebuliser and delivering it to patients’ lungs.
The chief executive is adamant that, should Molgradex be approved, doctors will choose Savara’s drug over the off-label option. He says that in aPAP, off-label GM-CSF is given by a standard nebuliser, “so you don’t really know how much drug is getting into the lung”, while Molgradex is given via a specialised device, Pari Pharma’s Eflow nebuliser, so delivery should be more predictable.
He also points to a parallel situation with tobramycin, an antibiotic for Pseudomonas infections. In lung infections doctors took a similar approach, delivering the intravenous version using a nebuliser off-label, but Mr Neville says they quickly switched to branded inhaled formulations such as the Tobi Podhaler once these became available.
He partly puts this down to caution about the safety of off-label drugs in a sensitive organ such as the lungs. “And there are reimbursement issues with off-label versus on-label drugs, even though [the latter] are more expensive.”
However, the Tobi Podhaler is hardly a massive product, and Novartis offloaded it to Mylan for $240m up front last year.
Before even thinking about launching, however, Savara has to produce a positive result in Impala, which is comparing two 300µg daily dosing regimens of Molgradex – continuously or one week on/one week off – against placebo in 135 aPAP patients.
The primary endpoint is change in alveolar-arterial oxygen difference (AADO2) at 24 weeks, effectively a measure of lung surfactant levels.
According to Mr Neville, a 6-8mmHg decrease in AADO2 is clinically meaningful, and this can be achieved with a single-sided whole lung lavage. Impala is 95% powered to show a 10mmHg reduction with Molgradex, although the chief exec reckons the project could better this. He notes that a study of off-label GM-CSF, at a lower dose than Molgradex, found a 12mmHg decline, so this is probably the bar that the Savara project needs to beat.
The key secondary endpoints of Impala are functional measures: change in the six-minute walk test and St George’s respiratory questionnaire, and time to whole lung lavage.
If Impala succeeds, Savara plans to file Molgradex in aPAP in the first half of 2020. Mr Neville believes that the opportunity here could be worth around $500m per year; EvaluatePharma sellside consensus puts 2024 sales at $329m.
Savara is also testing Molgradex for another use, nontuberculous mycobacterial (NTM) lung infections, which Mr Neville describes as “more speculative but much bigger”, although he will not say what the company hopes to achieve here.
This is where the comparison with Insmed comes in: that company's inhaled antibiotic, Arikayce, got the US FDA nod last year for Mycobacterium avium complex, a type of NTM infection. However, Molgradex, having a different mechanism, would not compete with Arikayce; indeed, Mr Neville believes the two approaches could be complementary. “We’re stimulating the immune system in the hope that it could clear infection,” he says.
The phase II Optima trial of Molgradex in NTM is ongoing; Savara reported encouraging interim results from 14 patients last year, and topline data from all 32 patients are due in the first quarter of 2020.
Savara has come a long way since acquiring Molgradex through its 2016 purchase of Serendex and reversing into Mast Therapeutics in 2017, a thrifty way of gaining a public listing. But the company has some way to go before it can claim to be in the same league as Insmed.