Vantage Snippets are short summaries of breaking news stories.

United pays $800m to enlarge its Arena

It seems obvious who got the best end of yesterday’s deal between Arena Pharmaceuticals and United Therapeutics. The former received $800m up front while the latter got the rights to yet another pulmonary arterial hypertension (PAH) candidate with a net present value of $327m, according to EvaluatePharma. Still, perhaps United, an expert in PAH, can get the most out of ralinepag, which some believe could have better efficacy than Johnson & Johnson’s marketed product Uptravi. Phase III data, due in 2021, could shed more light on whether this is indeed the case. United has been busy buying up rival projects of late: in September it swooped for Mannkind’s inhaled version of treprostinil, the same active ingredient used in United’s marketed PAH drugs Tyvaso, Orenitram and Remodulin. Ralinepag is at least slightly different, and the market reacted more positively to the Arena deal, sending United’s stock up 5% yesterday. Arena, meanwhile, climbed 22%, suggesting that both sets of investors believed their company had pulled off a coup. Arena now has the cash to advance its remaining wholly owned clinical-stage assets, etrasimod and olorinab, both in gastrointestinal indications. A third project, APD418 for heart failure, is in preclinical development.

Win-win? United and Arena's post-deal portfolios
Product Status Indication Mechanism of action 2017 sales ($m) 2024e sales ($m)
United's outlook
Remodulin Marketed Pulmonary hypertension Prostacyclin analogue 671 296
Orenitram Marketed Pulmonary hypertension Prostacyclin analogue 186 284
Ralinepag* Phase III Pulmonary hypertension Prostacyclin receptor agonist - 221
Tyvaso Marketed Pulmonary hypertension Prostacyclin analogue 373 215
Unituxin Marketed Neuroblastoma  Anti-GD2 MAb 76 98
Esuberaprost Phase III Pulmonary hypertension Prostacyclin receptor agonist - 73
Adcirca Marketed Pulmonary hypertension PDE 5 inhibitor 420 8
Treprostinil dry powder** Phase I   Pulmonary hypertension Prostacyclin analogue - -
Arena's outlook
Etrasimod Phase II Ulcerative colitis, Crohn's S1P receptor 1 regulator - 171
Olorinab Phase II IBD-associated pain CB2 agonist - 51
*Licensed from Arena; **Licensed from Mannkind. Source: EvaluatePharma.

Smiths forges ahead with medtech separation

Having failed on three separate occasions to sell off its underperforming medical devices business, Smiths Group is going to have another try at separating it out. The engineering conglomerate’s medtech unit, Smiths Medical, had sales of $1.3bn last year, but these are forecast to fall when it reports its 2018 figures. The separation is not a bad idea, and indeed has been awaited for some time, but the group has not said how it intends to get shot of Smiths Medical. A trade sale would be the preferable route, Deutsche Bank analyst say, but it is hard to say who might want to bid for the business, particularly since a stock-based deal with ICU Medical fell through in September. Previous attempts to sell the unit to Carefusion in 2013, and to the private equity group Apax Partners in 2011, also came to nothing. The alternative is of course an IPO, but whether shareholder demand is high enough to sustain yet another billion-dollar medtech float is unclear.

Smiths Group’s medtech business
  Global sales ($m)  
  2018 2020 2022 2024 CAGR
Anaesthesia & respiratory 329 344 361 378 +2%
Other medtech 748 781 820 859 +2%
Total medtech sales 1,077 1,125 1,181 1,237 +2%
Non-medtech revenues  3,138 3,386 3,642 3,898 +3%
Total company revenues 4,215 4,511 4,822 5,135 +2%
Source: EvaluateMedTech.

Merck injects new interest into Ebola vaccines

One could be forgiven for thinking that biopharma had given up on developing an Ebola vaccine following resolution of the big West Africa outbreak in 2014. But news that Merck & Co has begun the registration process for its candidate, V920, shows there is still interest in the deadly infection. And Merck is not the only big pharma with a horse in this race: data on a project from Johnson & Johnson and Bavarian Nordic should emerge next year. Meanwhile, Glaxosmithkline reportedly put its candidate, cAd3-EBO Z, on hold earlier this year, but has said it is monitoring the situation. Ebola outbreaks continue to occur – one, currently ongoing in the Democratic Republic of Congo, could last until mid-2019, the WHO said yesterday. While an effective vaccine could save lives, such products are unlikely to make a profit. But some see a different way to cash in on these assets: Newlink, which is partnered with Merck, could receive up to $40m for its share of a priority review voucher, Stifel analysts noted. After the failure of IDO inhibition, Newlink could do with the money.

Selected Ebola vaccines in active clinical development
Project Company Clinical trial(s) Primary completion
Filing begun
V920 Merck & Co NCT02503202 Completed
Phase III
Monovalent Ebola Vaccine Johnson & Johnson/Bavarian Nordic NCT02509494 Aug 2019
Phase I
INO-4201 Inovio Pharmaceuticals NCT02464670 May 2018
EBOV GP Vaccine Novavax NCT03462004* Oct 2019
*Sponsored by the NIAID. Source: EvaluatePharma,

Full data on Gelesis’s obesity pill are unsatisfying

Data from the Glow trial of Gelesis’s obesity therapeutic Gelesis100 looked mediocre when they were toplined more than a year ago; publication of the full dataset has not yielded anything more impressive. The product is a pill containing a cellulose-based hydrogel which expands in the stomach, occupying around a quarter of the volume. The trial hit one of its endpoints, with 59% of Gelesis100-treated adults achieving weight loss of at least 5% at six months, vs 42% in the placebo group. The other endpoint, placebo-adjusted weight loss super-superiority with a margin of 3%, was not met; the weight loss came in at 2.1%. The equivalent weight loss figures for other, approved, obesity devices range from 3.2% to 18%, though to be fair their administration can be more onerous. The average excess weight loss with Gelesis100 was 29%, again not hugely impressive versus its rivals. Gelesis has pointed to a “super-responder” group, which it says made up 27% of the Gelesis100 ITT population, who lost at least 10% of their bodyweight – but by that definition, 15% of the control group were super-responders to placebo. Gelesis, an affiliate of Puretech Health, has filed Gelesis100 with the FDA.

Concert’s value shaved after early alopecia win

Going up against Pfizer was always going to be tough. Concert Pharmaceuticals’ stock dropped 6% this morning despite promising signs from a mid-stage trial of its Jak inhibitor CTP-543 in alopecia, at least at the highest dose tested so far. Investors were concerned about CTP-543’s apparently slower onset than Pfizer’s rival Jak inhibitor PF-06651600, and on a conference call today Concert executives put this down to the phase II study of the Pfizer project using a loading dose during the first month that might have “jumpstarted” efficacy. CTP-543 appears to be effective at 8mg twice daily, but not at the 4mg twice-daily dose. The trial also has a 12mg twice-daily arm, but results from this will not be available until the third quarter of 2019. Concert will then decide which dose to take forward, and safety might be key. So far the company said there had been no cases of thrombosis, a worry with the Jak inhibitors, particularly those that target Jak2 such as CTP-543. If the 12mg dose improves efficacy but comes with a safety penalty, Concert’s value could shrink further.

Source: Company presentation

Mesoblast gets blasted again

The writing has arguably been on the wall for Mesoblast’s most valuable pipeline candidate, MPC-150-IM, since Teva walked away from the asset in 2016. Now a phase II failure has made the mesenchymal precursor cell project’s prospects look even dimmer. However, Mesoblast seems determined to limp on for a while longer, putting a positive spin on the flop, presented at the American Heart Association meeting on Saturday. The trial, in heart failure patients implanted with a left ventricular device (LVAD), did not meet its primary endpoint, which involved weaning subjects off LVAD support. But Mesoblast pointed to a “significant” reduction in major gastrointestinal bleeds with MPC-150-IM; the FDA, which has granted the project regenerative medicine advanced therapy designation, has described this endpoint as “clinically meaningful”, the company claimed. Investors were not convinced, sending Mesoblast’s shares down 29% today. A bigger test for MPC-150-IM awaits: a 600-patient phase III study in heart failure is around 85% enrolled. Failure here would surely wipe out all expectations for the project, which was recently among one of biopharma’s most valuable unpartnered assets, according to sellside numbers. 

Up next? Selected candidates in Mesoblast's mesenchymal cell therapy projects
Project Status Indication(s) 2024e sales ($m) NPV ($m)
Temcell HS Approved (Japan only) Graft versus host disease 29 1,520
MPC-150-IM Phase III Heart failure 715 1,137
MPC-06-ID Phase III Chronic low back pain 142 244
MPC-300-IV Phase II Rheumatoid arthritis, diabetic nephropathy, type 2 diabetes 59 56
Source: EvaluatePharma.

Pacific has not left Imfinzi at sea, Astra insists

Imfinzi’s Pacific study in stage III lung cancer raised doubts about giving the drug to all comers, given that it showed a numerically negative effect in a post hoc analysis of PD-L1-negative patients. But today Astrazeneca stressed that doctors in the US, who now have the greatest amount of experience, were largely prescribing Imfinzi in line with its all-comers label. PD-L1 expression is of interest, the group told this morning’s third-quarter media call, but is not being used to inform a decision on whether to use the drug. This year the EU regulator limited Imfinzi’s use in this setting to patients with PD-L1 expression of 1% or above, but no other agency has adopted this stance (World Lung 2018 – Pacific poses PD-L1 testing conundrum, September 27, 2018). Still, for some investors the NSCLC focus remains on metastatic disease, where the dominance of Merck’s Keytruda was one of the reasons behind today’s discontinuation of the mTOR inhibitor vistusertib, Astra suggested; one of its studies included KRAS-positive NSCLC. Imfinzi’s own first-line metastatic NSCLC trial Mystic, which failed on PFS, will yield topline OS data by the end of 2018.

Source: Astrazeneca Q3 presentation.

Voyager’s Parkinson’s gene therapy journey just got longer

Voyager Therapeutics is going full-steam ahead with a phase II trial of its Parkinson’s disease gene therapy candidate, VY-AADC. But yesterday the company poured cold water on hopes that this study might be enough for approval – and investors sent its stock down 12% in premarket trading. The company said in its third-quarter earnings announcement that the US FDA now considered the phase II study exploratory, appearing to row back from previous comments that, if successful, the trial might be enough for a filing. Although the topic dominated yesterday’s earnings call, Voyager’s chief executive, Andre Turenne, would only say that the company intended to meet the agency this year and that it had not changed its plan, which currently involves staggering the start of the phase II and III trials. Dosing is yet to begin in the 42-patient, placebo-controlled phase II study, which will evaluate an infusion of 2.5 x 10^12 vector genomes, between the mid and high doses used in VY-AADC’s phase I trial. That study found a promising response, measured using “on” time, with the middle dose, but disappointing results with the high dose; Voyager speculated that this might have been due to overactivity with the latter.

Selected novel Parkinson's disease projects in phase II development
Project Company Description Trial(s) Primary completion
ITI-214 Intra-Cellular Therapies PDE1 inhibitor NCT03257046 Reported
EPI-589 Sumitomo Dainippon Pharma Redox cofactor  NCT02462603 Dec 2018
Ferriprox Apotex Iron chelator Fairparkii, NCT02655315*; Sky, NCT02728843 Dec 2018; Aug 2019
Foliglurax Lundbeck mGluR4 regulator Ambled, NCT03162874 Apr 2019
Liraglutide (Victoza/Saxenda) Novo Nordisk GLP-1 receptor agonist NCT02953665* Jul 2019
CDNF Parkinson’s Project Herantis Pharma Cerebral dopamine neurotrophic factor NCT03295786 Aug-19
CX-8998 Cavion Calcium channel Cav3.2 blocker NCT03436953 Sep 2019
PRX002 Prothena Alpha-synuclein accumulation antibody Pasadena, NCT03100149 Mar 2020
VY-AADC Voyager Therapeutics AAV gene therapy NCT03562494 Dec 2020
GZ402671 Sanofi Glucosylceramide synthase inhibitor Moves-PD, NCT02906020 Mar 2021
BIIB054 Biogen Alpha-synuclein accumulation antibody Spark, NCT03318523 Mar 2021
*Investigator-sponsored. Source: EvaluatePharma.

Alnylam’s solo launch lives up to its mediocre billing

Another quarter has brought another timely reminder of how tough it is for biotechs to launch drugs without the assistance of a bigger partner with muscle. The RNAi product Onpattro, launched in August for polyneuropathy caused by hATTR amyloidosis, managed third-quarter sales of just $0.5m, missing expectations and sending its maker, Alnylam, down 12% yesterday. Consensus sellside forecasts compiled by EvaluatePharma have the drug selling $18m this year, something that now must surely be out of reach, notwithstanding Alnylam’s assurances that 125 US patient start forms had been received within seven weeks of Onpattro’s introduction. Barring outliers, biotech solo launches tend to disappoint the more optimistic investors, especially if a big pharma competitor is already on the market, as demonstrated recently by Clovis’s Rubraca – though interestingly not by Tesaro’s Zejula. Vantage had suggested in August that Alnylam would find going it alone tough (After Alnylam’s solo maiden launch, here comes the tricky bit, August 13, 2018). Goldman Sachs recently pointed out that rare disease drugs specifically tend to have disappointing launches, barring such big biotech products as Biogen’s Spinraza and Vertex’s cystic fibrosis franchise.

Mallinckrodt's VTS-270 flop puts Acthar back into focus

Anyone wondering what had happened to Mallinckrodt’s VTS-270 in Niemann-Pick C disease finally got their answer yesterday: its pivotal trial flopped. The company had been due to report results mid-year, but snuck out the news alongside third-quarter results. Mallinckrodt does not appear to have given up on VTS-270, which it gained through the $1.2bn acquisition of Sucampo: the company pointed to an unexpected lack of disease progression in the placebo arm of the study, adding that it would meet the FDA to see whether there was a path forward for the project. There is no cure for Niemann-Pick C disease, a rare genetic condition that leads to neurodegeneration and death. Assuming VTS-270 is a dud, hope now rests with Orphazyme’s arimoclomol citrate, due to yield data from a phase II/III trial in 2020. Meanwhile, it is a good job for Mallinckrodt that sales of its blockbuster, H.P. Acthar Gel, are declining more slowly than expected – and data are due next year in yet another indication, amyotrophic lateral sclerosis. But the VTS-270 failure makes Mallinckrodt’s pipeline look even less likely to make up for future Acthar losses.

Niemann-Pick disease clinical pipeline (all phase III)
Project Company Pharma class Subtype Trial Primary completion
VTS-270 Mallinckrodt Cholesterol modulator Niemann-Pick C NCT02534844 Failed
Arimoclomol citrate Orphazyme Superoxide dismutase 1 chaperone Niemann-Pick C NCT02612129 Oct 2020
Olipudase alfa Sanofi Human recombinant acid sphingomyelinase Niemann-Pick A/B  Ascend (NCT02004691) Jan 2024
Source: EvaluatePharma,
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