Vantage Snippets are short summaries of breaking news stories.
It has taken nearly two years, but the partial clinical hold placed on the intrathecal formulation of Novartis’s Zolgensma has finally been lifted. An intravenous form of the spinal muscular atrophy gene therapy is approved; the intrathecal version is intended to allow treatment of older patients. Novartis is to start a new pivotal trial, Steer, in treatment-naïve patients aged two to 18 with SMA type 2 who are able to sit, but have never walked. More than 100 patients will be randomised to either intrathecal Zolgensma or sham, and efficacy will be evaluated using the Hammersmith Functional Motor Scale-Expanded after a year. Reaching this older population is important: Novartis believes the intrathecal formulation could more than double the number of patients who could be treated with the gene therapy. So far over 1,400 patients have received intravenous Zolgensma worldwide. According to a survey of doctors conducted by SVB Leerink, were the intrathecal Zolgensma to gain approval for older Type 2 patients, around 25% of patients currently on maintenance therapy with Biogen’s SMA therapy Spinraza could switch to Novartis’s product. Still, intrathecal Zolgensma is not expected to reach market until 2024, even if Steer is a resounding success.
Astrazeneca has managed to bag US approval for anifrolumab in systemic lupus erythematosus, despite its mixed data package. The next question is whether the interferon type I inhibitor, now branded Saphnelo, can challenge the leading SLE therapy, Glaxosmithkline’s Benlysta. The latter has disappointed commercially since its launch in 2011 but is expected to finally become a blockbuster this year; sellside consensus compiled by Evaluate Pharma forecasts Benlysta sales of $1.5bn by 2026, versus Saphnelo’s $488m. At least Astra does not have too many other rivals breathing down its neck, a look at the late-stage pipeline shows. Interestingly, Biogen has two shots on goal here, having recently started pivotal development of its second contender, BIIB059. And Roche is also developing Gazyva in lupus nephritis, where Aurinia got approval of Lupkynis earlier this year. Meanwhile, a previous pivotal failure has not put off Immupharma, which is apparently now pushing Lupuzor into a second phase 3, funded by its partner Avion.
|The late-stage systemic lupus erythematosus pipeline|
|Olumiant||Lilly/Incyte||Jak 1 & 2 inhibitor||Brave II ends Oct 2021; Brave I ends May 2022|
|Dapirolizumab||Biogen/UCB||Anti-CD40L MAb||Phoenycs Go ends Feb 2023|
|BIIB059||Biogen||Anti-BDCA2 MAb||Topaz-1 ends Apr 2025; Topaz-2 ends Jun 2025|
|Gazyva||Roche||Anti-CD20 MAb||Allegory ends Nov 2025|
|Lupuzor||Immupharma/Avion Pharmaceuticals||Autophagy immunomodulator||Failed ph3 in Apr 2018, new ph3 planned|
|Source: Evaluate Pharma & clinicaltrials.gov.|
Last month saw plenty of setbacks for companies gunning for US approvals, with four complete response letters as well as a number of delays to Pdufa dates. One group that has been held up is Chemocentryx, which will now have to wait until October for the decision on Vynpenta for ANCA-associated vasculitis. The new date was given after Chemocentryx submitted a filing amendment intended to address issues raised during an earlier panel meeting. Having already been delayed to the third quarter, decisions on Jak inhibitors from Pfizer, Lilly and Abbvie have been pushed back again as the US regulators continue to review the safety profile of Pfizer's Xeljanz. The FDA has not given any guidance as to when the reviews might be completed. On a more positive note, Merck & Co’s Keytruda added more indications to its armoury, including neoadjuvant and adjuvant use in triple-negative breast cancer. However, the drug's accelerated approval in third-line gastric cancer was voluntarily withdrawn following an FDA-backed panel meeting in April.
|Notable first-time US approval decisions in July|
|Project||Company||Indication(s)||2026e sales by indication ($m)||Outcome|
|Bayer||CKD and type 2 diabetes||896||Approved|
|Kadmon||Chronic graft vs host disease||863||Approved (~6wks early)|
|Merck & Co/Ligand||Pneumococcal infection vaccine (adults)||786||Approved|
|Ibsrela (tenapanor)||Ardelyx||Control of serum phosphorus in adult patients with CKD||701||CRL|
|Chemocentryx||ANCA-associated vasculitis||639||Delayed to October 7|
|Saphnelo (anifrolumab)||Astrazeneca||Moderate to severe SLE||488||Approved|
|Albireo||Progressive familial intrahepatic cholestasis||299||Approved|
|Sulopenem etzadroxil/probenecid (oral sulopenem)||Iterum||uUTIs||220||CRL|
|Retifanlimab||Incyte||Squamous cell carcinoma of the anal canal||80||CRL|
|Dalvance||Abbvie||Acute bacterial skin and skin structure infections in paediatric patients||40||Approved|
|Provention Bio||Delay or prevention of type 1 diabetes in at-risk individuals||-||CRL|
|Gruppo Mediolanum farmaceutici||Acute steroid-resistant graft vs host disease||-||No decision yet|
|Fexinidazole||Sanofi/Drugs for Neglected Diseases initiative||All-oral treatment for sleeping sickness||-||Approved|
|Source: Evaluate Pharma & company releases.|
|Advisory committee meeting in July|
|Project||Company||Indication||2026e sales by indication ($bn)||Outcome|
|Anaemia due to CKD in adult patients not on dialysis and on dialysis||2.6*||The committee voted 12-2 against approval in pts on dialysis and 13-1 against approval for pts not on dialysis|
|Source: Evaluate Pharma & company releases. *Forecasts prior to adcom.|
|Supplementary and other notable approval decisions in July|
|Product||Company||Indication (clinical trial)||Outcome|
|Keytruda||Merck & Co||Locally advanced cutaneous squamous cell carcinoma that is not curable by surgery or radiation (Keynote-629)||Approved|
|Keytruda + Lenvima||Merck & Co/Eisai||Advanced endometrial carcinoma that is not MSI-H or dMMR (Confirmatory study Keynote-775)||Approved (~6wks early)|
|Keytruda||Merck & Co||High-risk early-stage triple-negative breast cancer plus chemo as neoadjuvant treatment and then as a single agent as adjuvant treatment after surgery (Keynote-522)||Approved|
|Keytruda||Merck & Co||Full approval triple-negative breast cancer (≥10% PD-L1 expressers) (Confirmatory study Keynote-522, originally granted in Nov 2020 based on Keynote-355)||Approved|
|Padcev||Seagen/Astellas||Regular approval and expanded indication in adult patients with locally advanced or met urothelial cancer who are ineligible for cisplatin-containing chemo (EV-301, EV-201)||Approved (~1mo early)|
|Darzalex Faspro + pomalidomide + dexamethasone||J&J||Adult multiple myeloma patients who have received at least one prior line of therapy (Apollo)||Approved|
|Octagram 10%||Octapharma||Dermatomyositis in adults (Proderm)||Approved|
|Prograf||Astellas||Prevention of organ rejection in adult and paediatric lung transplant recipients.||Approved|
|Bydureon BCise (exenatide extended-release)||Astrazeneca||Once-weekly injectable suspension for type 2 diabetes in paediatric patients ages 10 years and older (BCB114)||Approved|
|Shingrix||Glaxosmithkline||Prevention of shingles in immunocompromised adults||Approved|
|Semglee (Lantus biosimilar)||Viatris||Improve glycaemic control in adults and children with Type 1 diabetes and in adults with Type 2 diabetes (interchangeable label)||Approved|
|Botox||Abbvie||Label to include eight new muscles for the treatment of upper limb spasticity in adults||Approved|
|Nucala||Glaxosmithkline||Chronic rhinosinusitis with nasal polyps (Synapse)||Approved|
|Source: Evaluate Pharma & company releases.|
|Voluntarily withdrawn accelerated approvals|
|Keytruda||Merck & Co||3L (PD-L1 ≥1%) gastric/GEJ adenocarcinoma|
|Opdivo||Bristol Myers Squibb||2L hepatocellular|
|Source: Company releases.|
In another year, the takeout of Misonix by Bioventus might, at $518m, merit a place in the top 10 biggest medtech M&A deals. But 2021 has seen such a furious pace of dealmaking that Bioventus’s deal is only the 17th largest so far this year, according to Evaluate Medtech. Misonix makes therapeutic ultrasonic devices such as the BoneScalpel, used for osteotomy procedures; Bioventus will add these to its own orthopaedics and wound care products, selling to hospitals, ambulatory surgical centres and office care settings. Holders of Misonix stock can choose to receive either 1.7 shares of Bioventus class A common stock or $28 per share in cash. Bioventus expects the transaction to add nearly $80m to its calendar year 2021 revenue, and be accretive to its adjusted Ebitda in the first full year after the deal’s completion. The group is financing the purchase with a combination of cash and debt. Had Bioventus pulled the trigger earlier it might have got more of a bargain: at the half-year point Misonix’s share price was up 76% from the end of 2020.
What has Siemens Healthineers got right? Today the German group raised its guidance for the third time this year thanks to unexpectedly high sales of its rapid Covid-19 tests, just as almost every other test developer is reporting that sales of coronavirus assays are cratering. Healthineers posted sales of exactly €5bn ($5.9bn) for its fiscal third quarter, up 51%. Quarterly sales of its Covid-19 antigen tests were €600m, trouncing Berenberg analysts’ estimate of €250m. The group believes that demand for these tests will probably decline from here, though it reckons they will generate revenues of around €1bn in 2021, up from the €750m it forecast three months ago. The higher than expected sales of Healthineers’ coronavirus tests comes in sharp contrast to the falling sales of similar products reported by many other diagnostics makers. Abbott, a leading player in antigen tests for Covid-19 with its BinaxNow, Panbio and ID Now products, cut its full-year guidance by a quarter versus what it had forecast in April, blaming falling demand for these lines. And Qiagen slashed its 2021 guidance even more sharply, stating that its second-quarter Covid-19 sales had declined 17%.
|Selected Covid-19 test makers' guidance changes|
|Type of guidance||Full-year guidance given Q1||Full-year guidance given Q2||Change|
|Siemens Healthineers||Sales growth||14-17%*||17-19%**||16%|
|*Given fiscal Q2. **Given fiscal Q3. Source: company communications.|
Viatris’s Semglee was first approved last year, but its new interchangeable label means that it can be substituted for the reference product, Sanofi’s long-acting Lantus, at US pharmacies, like a generic. The FDA believes that this direct competition will cut prices; the amount US patients pay for insulin products has surged over the past few years. According to GoodRx, when bought without insurance a vial of Lantus costs around $190, versus around $110 for Semglee, though this pricing does not appear to take account of the new approval. But when a patient has insurance or Medicare coverage the calculation can become more complicated. In Sanofi's 2021 pricing report the company said that since 2012 the amount it received for Lantus had fallen 45% – but the average out-of-pocket cost for Lantus patients with commercial insurance and Medicare had risen 82%. Availability of a cheaper generic might simply mean that patients pay a similar amount and insurers pocket the difference. Perhaps more generics might help. Viatris will have a year on the market with Semglee before the FDA can approve another interchangeable biosimilar, but several non-interchangeable ones are available around the world, and some might eventually attain this additional label.
|Biosimilar versions of Sanofi's Lantus (insulin glargine)|
|Viatris||Semglee, Basalog||Launched in India in 2009, Japan in 2016, S Korea & UK in 2018 and Australia in 2019; approved in EU in 2018; approved in the US in 2020 and as interchangeable in 2021|
|Lilly/Boehringer Ingelheim||Basaglar, Abasaglar||Launched in South Korea in 2017; approved in EU & US in 2014 and in Australia & Japan in 2015|
|Samsung Bioepis||Lusduna||Approved in Europe in 2017; tentative US approval for follow-on biological granted in 2017|
|Gan & Lee||Basalin||Launched in China in 2005|
|Wockhardt||Glaritus||Launched in India in 2009|
|Kalbe Pharma||Ezelin||Launched in Indonesia in 2017|
|GC Pharma||Glarzia||Launched in S Korea in 2018|
|Source: the Generics and Biosimilar Initiative.|
“Never has the world been more conscious of the opportunity in adult vaccinations,” Glaxosmithkline’s Emma Walmsley told reporters today. Glaxo’s missteps in Covid-19 mean that the chief executive was referring to the company’s shingles and RSV efforts, two areas in which the pharma giant has huge hopes. In the former disease Glaxo has Shringrix, its most important growth driver, which has been derailed by pandemic vaccination programmes; demand is returning in the US but is proving slower to build elsewhere, second-quarter results revealed. Shringrix will remain closely watched this year, and needs to live up to executives’ bullish predictions for recovery. Glaxo also desperately needs to deliver pipeline progress in the wake of promises made to disgruntled shareholders. Two minor clinical setbacks were disclosed today – the failure of the Moonstone trial testing Zejula and Jemperli in a tough ovarian cancer setting, and another Icos setback for feladilimab. However, an investor presentation hints at little substantial news beyond Covid-19 until next year, and this will disappoint those demanding more urgency from the company. Future updates should at least include the first pivotal data in RSV, the company's most important pending readout from its most promising pipeline project.
Some investors must have been hoping that Adverum’s eye disease gene therapy still had a future after the alarming safety signal disclosed in April – hence today’s 18% downturn in the share price on news that ADVM-022 is to be shelved in diabetic macular oedema. Adverum revealed yesterday that four additional patients in the high-dose cohort of the phase 2 Infinity study also suffered clinically relevant low intraocular pressure. Adverum is taking no chances. Despite insisting that diabetic macular oedema and wet AMD had different causes, and that no cases of low eye pressure had been observed in wet AMD patients at any dose, it has also abandoned ADVM-022’s pivotal trial, Optic, in this disease. It plans to start a new phase 2 trial in wet AMD next year, using lower doses. But SVB Leerink analysts feel that there is no viable path for ’022 in wet AMD, an indication with very low tolerance for safety events and numerous highly effective therapies. Forecasts for ’022 sit at $96m in 2026, Evaluate Pharma data show, but the project seems likely to join Roche’s 4D-110 and 4D-125 and Biogen’s BIIB111 and BIIB112 on the ophthalmic gene therapy scrapheap.
Biomarin’s haemophilia A gene therapy valoctocogene roxaparvovec (valrox) was already under scrutiny over fading factor VIII levels. An update yesterday from its phase 1/2 trial, presented at the ISTH meeting, will have done nothing to allay those fears. At five years FVIII levels among seven patients treated with the highest dose, 6x1013vg/kg, had dropped to a median of just 8%. Biomarin will no doubt point to the fact that among six of these patients the mean annualised bleeding rate fell by 95% over this period and that, even at five years, 86% of patients had no bleeds. But it is still unclear how long valrox’s effect might last – not ideal for a supposedly once-and-done therapy that cannot be redosed. Valrox is already in a pivotal trial, Gener8-1, and an early look also suggested fading FVIII levels at two years. Two-year results on all participants in Gener8-1 are expected in early 2022. Biomarin might then be able finally to refile valrox, which was rejected by the FDA last year. However, even if it is approved, patients might choose to hang on for something better. Evaluate Pharma sellside consensus puts valrox’s 2026 sales at $695m, down from $1.8bn in April 2020.
|FVIII levels with 6e13 vg/kg dose of valrox over time: phase 1/2 results (NCT02576795)|
|Results all with chromogenic substrate assay. Source: company releases.|
Anyone who had been hoping for proof-of-concept data soon on targeting Tim-3 will be disappointed: readout from a study of Novartis’s sabatolimab, the most advanced Tim-3 project, has been delayed. The company had been expecting complete response data this quarter from the phase 2 Stimulus-MDS1 study in high-risk myelodysplastic syndrome, but today said a data-monitoring committee had concluded in June that the trial should remain blinded until its progression-free survival readout, slated for 2022 or 2023. CR and PFS are co-primary endpoints of the trial. The next most-advanced Tim-3-targeting asset, Glaxosmithkline’s cobolimab, is due to yield data from the phase 2 Amber study in the second half. The Novartis delay is unusual, and depending on the committee's criteria might be due to CR data being neither strong enough to unblind the study, or not sufficiently weak to declare it futile.
|Selected oncology projects targeting Tim-3|
|Sabatolimab||Novartis||Ph2 Stimulus-MDS1 readout delayed until 2022/23; ph3 Stimulus-MDS2 readout due 2023; ph2 Stimulus-AML1, ends Nov 2022|
|Cobolimab (TSR-022)||Glaxosmithkline (ex Tesaro)/ Anaptysbio||4 Ph2 dostarlimab combo studies, incl Amber readout H2 2021, Costar-Lung readout H2 2022|
|RG7769/ RO7121661||Roche||Tim-3/PD-1 bispecific, ph2 three-arm study incl RG6139 (PD1/Lag3 bispecific) and Opdivo ends Aug 2024, ph1 monotherapy, ends May 2023|
|Sym023||Les Laboratoires Servier||NCT03311412, anti-PD-1 combo, ends Nov 2021|
|BMS-986299||Bristol Myers Squibb||NCT03444753, +/- Opdivo/Yervoy, ends Nov 2021|
|BGB-A425||Beigene||NCT03744468, anti-PD-1 combo, ends Mar 2023|
|BMS-986258||Bristol Myers Squibb/Five Prime||NCT03446040, +/- Opdivo, ends Jul 2024|
|INCAGN2390||Incyte/Agenus||NCT04370704, anti-PD-1/Lag-3 combo, ends Jul 2023|
|SHR-1702||Jiangsu Hengrui Medicine||NCT03871855, +/- anti-PD-1, study status unknown|
|TQB2618||Sino Biopharmaceutical||NCT04623892, monotherapy, trial not yet recruiting|
|CA-327||Curis||Small-mol PD-L1/Tim-3 inhibitor, likely deprioritised|
|HLX52||Shanghai Henlius Biotech||–|
|Source: Evaluate Pharma & company releases.|