Vantage Snippets are short summaries of breaking news stories.

Fulcrum’s biopsy conundrum

Fulcrum’s shares tanked 48% yesterday after its lead project, losmapimod, faltered at an interim look in a progressive neuromuscular disorder, and further data next year need to impress to keep the project from the scrapheap. Biopsy results from the phase IIb Redux4 trial in 29 patients with facioscapulohumeral muscular dystrophy (FSHD) showed no separation from placebo at 16 weeks in DUX4-driven gene expression, and while a reduction in expression was hoped for in fact an increase was seen. FSHD is a caused by aberrant expression of DUX4 in skeletal muscle, leading to muscle death. Fulcrum was keen to point out that gene expression varies significantly throughout a patient's muscles, and in biopsies with high levels of DUX4 at baseline there were signs of a reduction. Data on 80 patients are due in the first quarter of 2021, and will include full-body MRI results, which Leerink analysts believe could capture losmapimod's impact across the body. Functional data are due in the second quarter. There are no disease-modifying treatments for FSHD, and for now Fulcrum has the lead project. 

Redux4 interim results change from baseline in DUX4 activity
  All subjects Highest expressing muscle biopsies
  Sample size Fold change Sample size Fold change
Losmapimod 15 3.7 3 -38.0
Placebo 14 2.8 5 -5.4
Source: company press release.

Ascensia throws Senseonics a lifeline

At the start of this year the continuous glucose monitor maker Senseonics was on the ropes, having run out of cash, stopped selling its products to new US customers and put itself up for sale. Enter Ascensia Diabetes Care's holding company PHC, which has provided a lifeline in the form of the purchase of $35m of convertible debt in Senseonics. The move will also see Ascensia, whose own glucose sensing technology is more basic, distribute Senseonics’ implantable glucose monitor. Ascensia will exclusively sell the Eversense device, which operates for three months, and Eversense XL, which works for six months, worldwide, and will also be the partner for products in development, including a year-long implantable sensor. PHC has the option of a $15m equity purchase on US approval of Eversense XL, possible next year. The tiny deal is not the takeout Senseonics might have hoped for, but this could be the result if the debt securities convert to equity and Senseonics' current investors are diluted. Senseonics has also arranged a separate financing deal worth up to $30m with Masters Special Situations, but its terms and structure are not disclosed.

Bayer hopes to sweeten its outlook with some Kandy

Fortune favours the brave, and embarking on an acquisition in the middle of a billion-dollar legal tussle is certainly a bold move. But arguably the $425m up front Bayer is spending on the private UK company Kandy Therapeutics is another way to strengthen its position in women’s health, a division that could use some new blood; despite holding significant market share, many of its lead contraceptives have lost patent protection. The company is also defending itself on the legal front, over injury claims for the implanted contraceptive device Essure. Today’s deal has been struck for NT-814, an oral neurokinin-1 & 3 receptor antagonist, for menopausal hot flushes and night sweats. Kandy was spun out of Nerre Therapeutics in 2017, and no investment beyond August 2018's £25m series C have been announced; if this is the extent of its funding the acquisition represents a very good return for investors. As for Bayer, whether this will yield an equally good return – the group has promised a further $450m in milestones – depends on NT-814 not only crossing the finish line, but generating the €1bn of peak sales Bayer is forecasting. Phase III trials start in 2021.

US de-authorises a second Covid-19 antibody test

US regulators’ efforts to double-check the accuracy claims manufacturers have made for their Covid-19 antibody tests have claimed another scalp. The emergency use authorisation awarded to Autobio Diagnostics’ Anti-Sars-CoV-2 Rapid Test in late April has been revoked after independent testing determined that “it is not reasonable to believe the product may be effective in detecting IgM antibodies” to the coronavirus. Autobio is thus no longer authorised to distribute the test. In its submission to the FDA Autobio claimed 99% sensitivity and specificity for IgG and IgM combined; tests conducted by the National Cancer Institute agreed with the specificity figure but found sensitivity to be 93%. The sensitivity for IgM alone was just 50%. Autobio’s is the second antibody test to have its authorisation rescinded owing to non-replicable accuracy claims; the first was Chembio’s, in June. With several authorised tests yet to undergo this independent investigation, there may well be more to come.

Note: "other" includes two antigen tests, two home sampling kits and one IL-6 test.

World Lung 2020 – Xcovery’s win might not save it from future competition

Beating Pfizer's first-generation Alk inhibitor Xalkori is becoming the clinical equivalent of kicking a puppy, and this weekend Xcovery put in its boot with a positive phase III readout in the head-to-head exalt3 trial of ensartinib. Rather than Xalkori, it is arguably more useful to look at ensartinib’s performance against fellow second-generation Alk inhibitors, and the positive result here is slightly less impressive. The duration of response Ensartinib achieved, which at 25.8 months was double that of Xalkori in the trial, is comparable on a cross-study basis with previous data from the current market leader, Roche's Alecensa, and Takeda's Alunbrig. As such, it is performance in brain metastases where the real battle lines are being drawn; here ensartinib was less notable, achieving response rates of 64%. Although ensartinib beat the 21% recorded by Xalkori, it is behind the respective 81% and 78% seen with Alecensa and Alunbrig, with the usual caveats about cross-trial comparisons. However, rather than these two products the real threat is expected to come from Pfizer’s follow up to Xalkori, Lorbrena, which is provisionally approved in patients who have not only failed on Xalkori, but on second-generation Alks too.  

Source: Dr Leora Horn & IASLC.
Source: Dr Christine Lovly (study discussant) & IASLC.

Risdiplam approval could spell more bad news for Spinraza

What is not to like about Roche and PTC's newly approved Evrysdi (risdiplam) for spinal muscular atrophy? Not only can it treat all-comers, regardless of age and disease severity, it is oral, has shown impressive efficacy and has been priced significantly below the two other approved SMA drugs. This makes Evrysdi a very compelling option despite it being third to market. Oral home administration is bound to play well during the Covid-19 crisis – its rivals Spinraza and Zolgensma have to be administered either in doctors’ offices or, in the case of Zolgensma, in clinics or hospitals. Then there are the patients who are not eligible for Zolgensma, or those who struggle with Spinraza’s thrice yearly spinal infusions. But the price of Evrysdi might be the biggest convincer; it is dependent on weight and capped at $340,000 per annum once a patient reaches 44 pounds, meaning that the cost for younger children will be much lower. Some analysts are already saying that Evrysdi could cut significant inroads into Spinraza’s current market lead among older patients, if not supplant it, with Zolgensma leading in type 1/2 SMA.

Approved SMA products
Product Patient population Annual/total list cost  2026e sales ($m)
Evrysdi All SMA types, all ages Up to $340,000 pa 1,545
Spinraza All SMA types, all ages $750,000 in first year, then 375,000 pa   1,174
Zolgensma Type 1/2 children aged two or under $2.1m one-off cost 1,872
Source: EvaluatePharma and company documents.

Aducanumab heads down the regulatory path

The FDA’s quick acceptance of aducanumab’s filing lifted Biogen’s shares 10% at the opening bell. A priority review was bestowed on the controversial Alzheimer’s project with a Pdufa set for March 7 next year. A decision could pan out earlier as the company stated that, if possible, the FDA could “act early on this application under an expedited review”. It will not all be plain sailing as an advisory committee meeting will be necessary, although no date has yet been given for this. Notably, Biogen said it had not used the priority review voucher it gained from its Spinraza approval, implying that the unmet need in Alzheimer’s had made this unnecessary and that the FDA had granted priotiry review based on aducanumab's merits. Biogen’s pipeline is thin, though it was bolstered yesterday by a deal with Denali, and aducanumab remains Biogen’s biggest growth driver. The group is now one step closer to the endgame.

Another disappointing result for Tecentriq in triple negative breast cancer

Anti-PD(L)-1 antibodies have a mixed record in triple negative breast cancer, and the failure of Impassion131, a first-line trial of Roche’s Tecentriq, is another black mark. Tecentriq failed to improve PFS versus paclitaxel in PD-L1-positive patients, Roche said, while a negative trend on overall survival, a secondary endpoint, was detected. The trial was not sufficiently powered to show a benefit here and the data are still immature, but the study had already been upsized and the readout delayed, suggesting that the company was struggling to tease out even a marginal benefit. Tecentriq has accelerated approval in the US as a first-line treatment of TNBC in patients with least 1% PD-L1 expression, based on the Impassion130 trial. This was similar in design to Impassion131, but recruited more patients and used Abraxane instead of paclitaxel as the chemo comparator. There is some suggestion that paclitaxel could have made a difference: the high dose steroid premedication required to stave off side effects has been associated with diminished efficacy of immunotherapies. Tecentriq’s success in a neoadjuvant TNBC study earlier this year arguably makes the Impassion131 failure less important, but it is clear that there is still much to be learned about the drug's role in this disease.

Roche trials in triple-negative breast cancer
Study Design Primary endpoint(s) Result
Impassion-031 Tecentriq + Abraxane vs Abraxane pCR in PD-L1+ and all-comers Toplined positive in PD-L1+ and all-comers
Neoadjuvant + adjuvant
NeoTRIPaPDL1  Tecentriq + Abraxane vs Abraxane EFS Failed in Dec 2019
MO39875 Tecentriq + chemo vs chemo pCR & EFS Dec 2023 primary completion
Impassion-030 Tecentriq + chemo vs chemo iDFS Jan 2022 primary completion
Impassion-130 Tecentriq + Abraxane vs Abraxane OS & PFS in PD-L1+ and all-comers Approved in ≥1% PD-L1
Impassion-131 Tecentriq + paclitaxel vs paclitaxel PFS in PD-L1+ and all-comers Failed in Aug 2020
Impassion-132 Tecentriq + chemo vs chemo OS in PD-L1+ and all-comers Upsized by 63%, completion delayed from Jul 2019 to Jan 2023
Ipatunity-130 Ipatasertib + chemo vs chemo PFS in PIK3CA/AKT1/PTEN-altered Dec 2021 primary completion
Source: & company presentation.

Novo Nordisk sticks to conservative obesity sales target as data impress

Novo Nordisk is sticking to its goal of doubling obesity sales by 2025, but impressive results from its two lead projects makes this target look beatable. Results from semaglutide's Step programme and two trials of the amylin receptor agonist AM833 were detailed today, and executives said the data “strengthens their confidence” in the target being hit, but declined to say whether hopes were now higher. Results from a combination trial are particularly strong: 66% of patients who took the highest dose lost more than 15% of their body weight over 20 weeks. Tolerability was similar to semaglutide monotherapy, which as a GLP-1 agonist is largely GI issues. The combination has the potential to offer a noninvasive alternative to bariatric surgery, the company believes, and a pivotal trial is slated to start next year. Semaglutide will be filed at the end of this year. The combination data “raised the bar” for future obesity treatments, Novo said, hence the termination of two pipeline projects, a GG-co-agonist and tri-agonist. The sellside already expects Novo to beat its obesity sales target, suggesting that should this efficacy hold up in phase III, these numbers have the potential to go a lot higher.

Novo Nordisk Q2 investor presentation.

Eliquis patent win adds a few billion to Bristol and Pfizer

Losing the Eliquis patent fight would have been extremely costly for Bristol Myers Squibb and Pfizer and investor relief was palpable this morning: shares in the respective companies jumped 2% and 3% at the open, adding a couple of billion dollars to market caps. Eliquis’s composition of matter patent expires in 2026 although a formulation patent stretches out to 2031 – both were upheld by a US district court yesterday. Bristol has settled with a number of generic challengers which are likely to launch well before 2031, but this win secures sales up to 2026, with the caveat that an appeal is likely. On a call today executives hinted that generics might be delayed beyond 2027, which is when they are expected to arrive; should this come to pass, the win here would be even bigger. The oral blood thinner is Bristol’s biggest growth driver by some margin, with sales expected to top $10bn this year and peak at $13bn in 2025, while it counts as Pfizer's third-largest source of income. The drug overtook Bayer and Johnson & Johnson’s Xarelto to become the biggest selling novel oral anti-coagulant in 2018, and sales have consistently beaten expectations since.