Vantage Snippets are short summaries of breaking news stories.
Relying on uncontrolled trials is a risky business. GTX has demonstrated this again with failure in the first placebo-controlled study of its stress urinary incontinence candidate enobosarm. This looks like the end for the project and the company, too: after enobosarm, GTX’s most advanced assets are preclinical selective androgen receptor degraders for prostate cancer, and the group only had $46m at the last count. GTX’s stock plunged 91% this morning, wiping out gains seen since the company reported positive data from its uncontrolled proof-of-concept trial a year ago. Today’s result from the Astrid trial demonstrates why including a placebo group is so important: 53% of patients in the control arm achieved the primary endpoint, a 50% reduction in stress incontinence episodes at 12 weeks, versus a 60% and 58% response in the 3mg and 1mg enobosarm arms respectively. This is not much of a consolation for patients with stress urinary incontinence, whose only options are pads, pelvic floor exercises and surgery. The enobosarm failure means that this is unlikely to change for a long time – Stifel analysts noted that the project was the only one in development for the disorder, which affects around one third of postmenopausal women.
After months in the wilderness Acadia has avoided the worst-case scenario of getting its sole product, Nuplazid, pulled from the market. The FDA has concluded that there are no new safety risks with the drug, which is approved for hallucinations and delusions associated with Parkinson’s disease psychosis. This should go some way towards repairing the damage done by a CNN article in April citing a high number of deaths with Nuplazid (Acadia can’t shake off its Nuplazid nightmare, July 10, 2018). But Acadia is not out of the woods just yet, despite a 27% jump in its share price yesterday and another climb of 6% today. Lingering safety fears could continue to hit Nuplazid sales – particularly as the FDA’s release noted that, in many cases, there was not enough information to ascertain whether patient deaths had been drug related. The report also noted “potentially concerning prescribing patterns”, such as use of Nuplazid alongside other drugs that can cause QT prolongation, going against warnings on the product’s label. If Nuplazid is to bring in sales of $2.2bn in 2024, as forecast by EvaluatePharma sellside consensus, Acadia will need to convince doctors and patients that any persistent safety worries are unfounded.
|Selected Nuplazid adverse events|
|Note: *cases where Nuplazid is listed as "primary suspect"; numbers are duplicated if hallucination and death occurred in the same subject. Source: Advera Health Analytics.|
The non-invasive prenatal testing specialist Premaitha Health is the most recent company to discover that legally discretion is the better part of valour, having signed a licence with the sequencing giant Illumina that puts to rest the companies’ long-running patent dispute. Premaitha will now develop a version of its Iona test, which detects circulating foetal DNA in the mother’s blood to diagnose Down’s, Edwards and Patau syndromes and runs on Illumina sequencers. The aim is to get this CE marked and launched by early 2020, whereupon Premaitha will be free to sell it in countries including those covered by the European Patent Convention. The UK group will pay Illumina a royalty for each sample tested using the new form of Iona, but before that will hand over settlement fees approaching £1m ($1.3m). The 11% rise so far today in Premaitha’s share price suggests that investors are willing to tolerate this outlay in exchange for a more secure future.
News of a patient death and a partial clinical hold for Mersana Therapeutics’ Her2-targeting antibody-drug conjugate XMT-1522 sent the group’s stock down 32% in July. But the lifting of that hold did not provide relief – in fact, Mersana’s shares fell 23% yesterday. More monitoring and the exclusion of patients with liver damage led to fears of further delays to the resumed phase I study. Mersana is taking a similarly cautious approach with its follow-up project, XMT-1536, an ADC targeting NaPi2b that was not subject to a clinical hold; but the trial changes raise questions about the safety of the company’s entire platform. Safety concerns have derailed several ADCs, which are designed to dump a toxic payload on tumours expressing a certain target. Since targets like Her2 are also expressed in healthy tissue perhaps it is not surprising that problems have arisen. In contrast to Mersana, Sosei was virtually unmoved today after its UK subsidiary Heptares and Allergan suspended development of their phase I Alzheimer’s project, the muscarinic M1 receptor agonist HTL18318. The move, prompted by a tumour seen in a primate study, will delay the start of phase II trials by at least six months, Sosei said.
The $15m up front Novocure received from Zai Lab for a Chinese licence to its Optune device is less important than the strategic advantages the deal produces. Zai Lab will pay a 10-15% royalty on Chinese sales of the device, which is already approved in Europe, the US and Japan for glioblastoma. Zai Lab will help accelerate China-based trials in other cancers – Optune is in phase III trials in pancreatic and non-small cell lung cancers, and a phase III pivotal study in ovarian cancer is planned for later this year. Zai Lab will also start a Chinese phase II trial of the device in gastric cancer. Wells Fargo analysts say that Optune’s approval in mainland China is likely in the second half of next year. The product is expected to be priced more cheaply in China than in the US, where it goes for $21,000, but since the Chinese glioblastoma market is three times the size of the US opportunity it could still do well. With Zai Lab on side Novocure could break the $1bn sales mark ahead of the currently forecast date of 2023.
|Novocure' forecast sales|
|WW annual sales ($m)|
|Total company revenues||377||531||675||824||973||1,122||1,271||+22%|
With today’s approval of Astrazeneca’s Lumoxiti the US market has two antibody-drug conjugates against the CD22 antigen. While the first, Pfizer’s Besponsa, was approved a year ago for treating relapsed adult acute lymphoblastic leukaemia (ALL), Astra has positioned Lumoxiti against hairy cell leukaemia, a relatively rare malignancy. Both these haematological cancers affect B cells, hence the relevance of hitting CD22, an antigen present on this cell lineage. An important difference between Besponsa and Lumoxiti is the cytotoxic payload each carries – respectively calicheamicin, the same as that used in Pfizer’s Mylotarg, and Pseudomonas exotoxin A. And both drugs’ labels carry boxed warnings, respectively for liver damage and capillary leak syndrome, the toxicity that briefly derailed Stemline’s anti-CD123 conjugate SL-401. The next anti-CD22 asset to test the regulators could be Immunomedics’ epratuzumab, though as this is a standard “naked” antibody it is unlikely to match the efficacy of more advanced constructs like conjugates and bispecifics. The big competitor could emerge in the form of CD22-directed CAR-T therapy, though this is still some way off being commercialised.
|Anti-CD22 antibody-drug conjugates|
|Project||Pharmacology class||Company||Lead indication||2024e sales ($m)|
|Besponsa (inotuzumab ozogamicin)||Anti-CD22 MAb-calicheamicin conjugate||Pfizer/ UCB||ALL||519|
|Lumoxiti (moxetumomab pasudotox)||Anti-CD22 MAb-PE38 conjugate||Astrazeneca||Hairy cell leukaemia||218|
|Pinatuzumab vedotin||Anti-CD22 MAb-monomethyl auristatin E conjugate||Roche/ Seattle Genetics||NHL||NA|
|BAY1862864||Anti-CD22 MAb-thorium 227 conjugate||Immunomedics/ Bayer||NHL||NA|
|ASCT-602||Anti-CD22 MAb-pyrrolobenzodiazepine conjugate||ADC Therapeutics||NHL, ALL||NA|
|TRPH-222||Anti-CD22 MAb-4AP drug conjugate||Triphase Accelerator/ Celgene||NHL||NA|
|ALL=acute lymphoblastic leukaemia; NHL=non-Hodgkin lymphoma; NA=not available. Source: EvaluatePharma.|
Supernus needs fresh blood as its migraine drug Trokendi XR faces pressure from anti-CGRPs and approaches the end of its patent life. But investors had clearly hoped that the company would use its huge cash pile to strike a bigger deal than yesterday’s $15m bet on Biscayne Neurotherapeutics; Supernus shares dropped 1% in premarket trading today. Biscayne’s sole project, BIS-001ER – now known as SPN-817 – is in a phase I/II trial in adults with epilepsy, and Supernus plans to develop it in rare childhood epilepsies such as Dravet syndrome. The company must hope that current Dravet candidates like GW Pharmaceuticals’ cannabis-derived project Epidiolex and Zogenix’s low-dose fenfluramine pill ZX008 will leave room for improvement. Epidiolex was approved this year, and ZX008 could join it in 2019. At least the Biscayne deal fits squarely within Supernus’s focus on epilepsy and extended-release formulations: SPN-817, a synthetic version of the acetylcholinesterase inhibitor huperzine A, could get around the serious side effects seen with immediate-release forms, the company believes. While SPN-817 is still early, Supernus has a couple of later-stage bets, and is due to report data from three of four pivotal trials of its ADHD project SPN-812 by the end of the year.
|Replacing Trokendi XR – Supernus's pipeline|
|Trokendi XR||Marketed||Epilepsy, migraine||227||100|
|SPN-810||Phase III||Impulsive aggression in ADHD||-||289|
Boehringer Ingelheim struck a deal with the oncolytic virus company Viratherapeutics in 2016, and it has clearly seen something extraordinary in the intervening two years. Otherwise it would be difficult to understand why it would today shell out €210m ($245m) to exercise an option to buy out Viratherapeutics without having seen a scrap of clinical data. It is clear that big pharma sees oncolytic viruses as an increasingly important part of the anticancer combination armoury. The previous deal, in February, saw Merck & Co pay a 184% premium to take out Viralytics for $394m, though unlike Viratherapeutics this company had a phase II asset (Merck & Co makes biggest oncolytic virus bet since Amgen in 2011, February 21, 2018). True, Amgen’s 2011 buyout of the Imlygic originator Biovex for $424m is a long way from being declared a masterstroke, but the potential of oncolytic viruses in immuno-oncology combinations is now increasingly being talked about – specifically in terms of turning “cold” tumours “hot” – and indeed Boehringer says this dual approach is central to its cancer immunology research strategy. Expect increased interest in other oncolytic virus companies, such as Targovax, Transgene and Oncolytics.
|Selected oncolytic virus deals|
|Sep 2018||Viratherapeutics||Boehringer Ingelheim||Acquisition||$245m||VSV-GP project, preclinical|
|Feb 2018||Viralytics||Merck & Co||Acquisition||$394m||Cavatak, phase II asset|
|Nov 2017||Oncolytics||Adlai Norte||Licensing||$5m||Far East development of Reolysin|
|Oct 2017||Turnstone Biologics||Abbvie||Licensing||Undisclosed||Ad-MG1-MAGEA3, phase I/II asset|
|Dec 2016||Ignite Immunotherapy||Pfizer||Acquisition||Undisclosed||50% stake|
|Dec 2016||Psioxus||Bristol-Myers Squib||Licensing||Undisclosed||NG-348, preclinical asset|
|Dec 2016||Takara Bio||Otsuka||Licensing||Undisclosed||Japan rights to HF10|
|Nov 2016||Virttu Biologics||Sorrento||Acquisition||$25m (equity)||Seprehvir, phase II asset|
|Jun 2016||Psioxus||Bristol-Myers Squib||Licensing||$10m||Enadenotucirev, phase I collaboration|
|Jun 2015||Oncos||Targovax||Acquisition||Undisclosed||Structured as a 50/50 merger|
|Jan 2015||Omnis||Astrazeneca||Licensing||Undisclosed||VSV project, phase II|
|Nov 2013||Jennerex||Sillajen||Acquisition||Undisclosed||$150m biodollar value|
|Jan 2011||Biovex||Amgen||Acquisition||$424m||Imlygic, approved for melanoma in 2015|
|Source: company statements.|
Being a one-product company is all very well until that one product collapses. The phase III failure of Elad, a cell therapy for acute liver failure developed by Vital Therapies, was so incontrovertible as to force the company to abandon the project. Investors abandoned Vital in turn, scything 88% from the company’s value and leaving it with a market cap of just $32m. Elad consists of four cartridges collectively containing 440g of human-derived liver cells from Vital’s cell bank. According to Vital’s website, blood is drawn from the patient and pumped through the Elad system, where the cells absorb toxins and release “potentially beneficial macromolecules” into the blood, which is then reinfused into the patient. The process requires a single, continuous five-day session. The VTL-308 study, testing Elad in 151 patients with alcohol-induced liver decompensation, failed to show an overall survival advantage for the product over standard of care at 91 days. The trial also missed its secondary endpoint, showing no difference between the groups in the proportion of survivors at day 91. The end of Elad likely means the end of Vital as a going concern: the UK group is exploring strategic options.
If at first you don’t succeed, do a bigger study. Foamix has finally shown a statistically significant benefit with its acne foam, FMX-101, in a third – and substantially upsized – phase III trial. But the numerical benefit, while slightly better than that seen in the two previous pivotal failures, is not much wider than in previous trials. Foamix plans to file a new drug application on the latest data, which might be enough for approval, but there is still the question of how big the market for FMX-101 is – a similar-looking topical prescription acne product, Aczone, recently acquired by Almirall from Allergan, made $174m in 2017. Another question is whether Israel-based Foamix, which had just $56m in cash at the end of June, would be able to launch FMX-101 alone – something it previously told Vantage that it planned to do, at least in the US. Still, with the group’s stock rising 54% in premarket trading this morning, back to levels seen before the project flunked the smaller phase III studies, a fundraising looks imminent.
|Foamix's phase III trials of FMX-101|
|Trial 04 (NCT02815267)||Trial 05 (NCT02815280)||FX2017-22 (NCT03271021)|
|Placebo-adjusted change in no. inflammatory lesions||2.99 (p=0.0071)||2.74 (p=0.0058)||3.53 (p<0.0001)|
|Placebo-adjusted IGA success (percentage points)||3.32 (p=0.2178)||6.78 (p=0.0423)||11.17 (p<0.0001)|
|All data at 12 weeks; Source: Company press releases.|