Vantage Snippets are short summaries of breaking news stories.
The annual drug review released by China’s medicines regulator, the Center for Drug Evaluation or CDE, is highly technical and packed full of information – not all of which is translated into English. But the document provides some interesting insights into the work of the agency and the country’s pharmaceutical industry, and Vantage has extracted a couple of titbits. The first graph below shows applications to start clinical trials and approval filings, all of which have grown over the past six years. The jump in biological INDs is most notable; this contrasts with a much smaller advance in the number of biotech-based projects filed for approval, which will presumably accelerate in the coming years. The second chart shows that, as in the west, a huge proportion of the sector’s research spending is directed at cancer, though it is important to note that these data only cover small molecules. The equivalent data on all biotech-based projects could not be extracted from the report reliably. Finally, the big jump in IND approvals overall in 2017 and 2018 could possibly be explained by the venture capital boom, from which China-based start-ups have benefited.
A 16% jump in Nordic Nanovector shares will be welcomed by long-suffering investors, who have seen the stock lose two thirds of its value since the end of 2016 on a series of delays to the company’s lead project, Betalutin. This radionucleotide is in a third-line, follicular lymphoma phase IIb trial, on which the company hopes to file. An update from the first stage of the study, showing lengthening duration of responses, prompted the share uptick today. However, there is a sting in the tail here: longer timelines mean that Nordic Nano does not have enough money to finish the trial. Little has been said about how or when fresh funds will be raised; an interim readout due early next year could serve as a trigger, but presumably the company needs to act sooner, as current cash will only last until mid-2020. Recruitment is expected to complete in the second half of next year, with readouts in early 2021 – 18 months later than was initially intended. Delays have cost the company a chief executive as well as investor support, and in the meantime the competitive environment has stiffened. Today’s share price rise could be short lived.
|Selected late-line follicular lymphoma projects|
|Project||Company||Mechanism||Details||Consensus for lymphoma sales in 2024 ($m)*|
|Aliqopa||Bayer||Pan-PI3K inhibitor||Acclerated approval based on 59% ORR (N=104)||115|
|Zydelig||Gilead||PI3K delta inhibitor||Acclerated approval based on 54% ORR (N=72)||83|
|Copiktra||Verastem||PI3K delta & gamma inhibitor||Acclerated approval based on 42% ORR (N=83)||88|
|Tazemetostat||Epizyme||EZH2 inhibitor||Filed on 77% ORR (N=43)||538|
|ME-401||MEI Pharma||PI3K delta inhibitor||ORR of 75% in phase Ib (N=30); pivotal phase II recruiting||188|
|Betalutin||Nordic Nanovector||CD37-targeting radionucleotide||ORR of 70% in phase I (N=37); pivotal phase II recruiting||107|
|REGN1979||Regeneron||CD20-CD3 bispecific||ORR of 93% in phase I (N=21); pivotal phase II recruiting||N/A|
|INCB50465 (parsaclisib)||Incyte||PI3K delta inhibitor||ORR of 71% in phase I (N=4); pivotal phase II recruiting||n/a|
|*Estimates based on all sales in non-Hodgkin lymphoma, of which follicular lymphoma is only one subtype. Source: EvaluatePharma & Nordic Nanovector presentation.|
Acceleron is taking the admirable step of discontinuing its lead wholly owned asset, ACE-083, in facioscapulohumeral muscular dystrophy (FSHD) after mixed results from a phase II trial. Many biotechs might have continued given that the study met its primary efficacy endpoint, showing an increase in mean muscle volume; however, the trial did not hit functional secondary endpoints. Acceleron’s willingness to cut its losses sent its stock down only 1% this morning, and a look at the group’s upcoming catalysts shows that it has plenty more irons in the fire. Still, many of these events involve luspatercept, which is partnered with Celgene, with Acceleron only due minimal milestones, plus royalties. ACE-083 will also soon yield data in another neuromuscular disorder with a different pathophysiology, Charcot-Marie-Tooth disease; however, the sellside does not forecast any sales in this indication, according to EvaluatePharma. ACE-083 inhibits TGF-beta proteins such as myostatin with the aim of increasing muscle mass and strength; its failure could be bad news for similarly acting projects including Scholar Rock’s SRK-015 and Roche/Bristol-Myers Squibb’s RG6206. in April Acceleron discontinued another TGF-beta inhibitor, ACE-2494, which had been in phase I development for neuromuscular disorders.
|Acceleron's upcoming catalysts|
|Project||Indication||Event||Note||2024e indication sales ($m)|
|ACE-083||Facioscapulohumeral muscular dystrophy||Phase II data (NCT02927080)||Failed, discontinued||9|
|Luspatercept||Myelofibrosis||Phase II data (NCT03194542)||Data due H2 2019||-|
|Luspatercept||Transfusion-dependent beta-thalassaemia||FDA approval decision||Dec 4, 2019||340*|
|ACE-083||Charcot-Marie-Tooth Disease||Phase II data (NCT03124459)||Data due Q1 2020||-|
|Sotatercept||Pulmonary arterial hypertension||Phase II data (Pulsar, NCT03496207)||Data due Q1 2020||46|
|Luspatercept||Second-line MDS with ring sideroblasts||FDA approval decision||Apr 4, 2019||615**|
|Sotatercept||Pulmonary arterial hypertension||Phase II data (Spectra, NCT03738150)||Data due 2020||46|
|Luspatercept||Non-transfusion-dependent beta-thalassaemia||Phase II data (Beyond, NCT03342404)||Data due 2020||340*|
|Luspatercept||First-line MDS||Phase III data (Commands, NCT03682536)||Data due H2 2020||615**|
|*Overall beta-thalassaemia sales; **overall MDS sales. Source: EvaluatePharma, clinicaltrials.gov.|
|Select myostatin inhibitors in clinical development|
|Project||Company/ies||Indication||Trial details||Primary completion|
|RG6206||Roche/Bristol-Myers Squibb/Chugai||Duchenne muscular dystrophy||NCT03039686||Dec 2020|
|SRK-015||Scholar Rock||Spinal muscular atrophy||Topaz, NCT03921528||Jan 2020|
|BIIB110||Biogen||Spinal muscular atrophy||?||-|
|Source: EvaluatePharma & clinicaltrials.gov.|
Purdue Pharma as we know it is no more: last night the company said it had had filed for bankruptcy. The move effectively sees Purdue hand over $10bn, and what would have been years of litigation over potential opioid abuse settlements, to the bankruptcy courts. However the group’s demise makes it even more curious that Mallinckrodt, once described as the “kingpin of the drug cartel”, might have escaped a similar fate by so far paying just $24m to settle legal claims in two counties in Ohio. While the $24m only absolves the company from further claims in Cuyahoga and Summit counties, it does buy Mallinckrodt time to achieve its ultimate aim – a global settlement of all opioid lawsuits. Until Mallinckrodt’s agreement in early September, many had predicted that the group would also file for bankruptcy. Purdue’s passing, however, seems inconsistent. Notwithstanding the focus on the company and the associated Sackler family, Mallinckrodt had a much bigger share of opioid sales in the US through generic versions of Oxycontin and hydrocodone. Those looking for the next scalp in the US opioid crisis might wonder why Mallinckrodt has so far escaped so lightly, apart from its share price fall.
Aimmune shares sank 5% in early trade today despite a largely positive US FDA advisory committee hearing on Friday for its peanut allergy immunotherapy, AR101; the outcome means that approval in January looks likely. But investors’ reaction shows how prospects for the project, to be branded Palforzia, are still very hard to call, even before considering the usual concerns about a solo launch by a small company. Factors in Aimmune’s favour include a relatively large and motivated pool of patients and a dataset that many believe establishes Palforzia’s safety and effectiveness, at least in the short term. Questions remain about long-term benefits, however, particularly versus peanut avoidance; a critical report by the cost watchdog Icer raised this point earlier in the year and, although it was widely dismissed by the company and supportive analysts at the time, payers will look closely at the issues raised when Palforzia’s price emerges. EvaluatePharma’s consensus revenue forecast shows that the sellside expects commercial success, though even here the spread of numbers shows that views vary considerably. It seems that not all investors want to wait around to find out how AR101 actually fares in the market.
Enrolment in the phase I trial of Amgen’s AMG 397 in various blood malignancies has been placed on hold, the group said yesterday, after a cardiac toxicity signal was seen with the myeloid cell leukemia-1 (MCL-1) inhibitor. No further details on the safety signal were given but Amgen also felt the need to stop enrolment in a phase I study of its second MCL-1 inhibitor, AMG 176, in acute myeloid leukaemia. MCL-1 is thought to be highly expressed in many cancers and has been implicated in the development of resistance to therapy. In a phase I study with AMG 176 in relapsed or refractory multiple myeloma, treatment-emergent adverse events of grade 3 or higher occurred in 62% of patients, the most common of which were neutropenia, anaemia and hypertension. Although no cardiac toxicity has been disclosed here, there were two fatal adverse events in the study, one of which was due to treatment. Astrazeneca and Novartis are also developing drugs with this mechanism, but it could be a wasted journey if toxicities turn out to be a class effect.
|Inhibitors of Mcl-1|
|Phase I||AMG 397||Amgen||NCT03465540
Signs of history repeating itself has appeared from Adverum, an optical gene therapy company that spectacularly crashed as Avalanche four years ago. A press release announcing six month data from six wet AMD patients treated with its gene therapy, ADVM-022, focused on the lack of anti-VEGF rescue medicines needed. Investors, however, were more concerned by the deterioration of vision that these subjects suffered. Best corrected visual acuity (BCVA) results showed a worsening of vision with a mean change of -2 letters. This raised questions over whether patients should have received rescue injections; the company responded that subjects did not reach the criteria for rescue jabs, and that the vision loss was not down to wet AMD disease activity anyway. Several reports of ocular inflammation only added to worries about this data set - Adverum shares closed down 50%, erasing $390m from the company's market value. A second cohort using a lower dose will report next year, but hopes are low that these data will offer any redemption on today’s results.
The Impower-110 trial testing Roche’s Tecentriq as a monotherapy in first-line non-small cell lung cancer has hit, significantly improving overall survival versus chemo. The trial enrolled patients with squamous or non-squamous tumours and high PD-L1 expression: selecting these patients should have increased the study's chance of success, but confirmation will still come as a relief to the company after other setbacks in this setting. Tecentriq could become the second anti-PD-(L)1 to gain single-agent approval in first-line NSCLC, after Keytruda – though of course given that the Merck & Co antibody is already well entrenched here, this accolade will probably not count for much. Much depends on the magnitude of the benefit that Tecentriq has shown, though this has yet to be disclosed; a look at what Keytruda has shown in this setting gives an indication of what Tecentriq will need to beat. The graph below, taken from EvaluatePharma’s consensus sales forecasts, includes all NSCLC settings, and shows Keytruda’s lead here to be almost unassailable, no matter how good the full dataset from Impower-110 turns out to be.
|PD-(L)1 Monotherapy NSCLC trials|
|PD-L1 limit||≥50%||≥1%||TC or IC ≥ 1%|
|Data||Median OS: 30 mths. HR=0.60.||Median OS: 16.7 mths. HR= 0.81.||Hit on OS|
|Source: Drug labels, company releases.|
A week ago Tocagen’s chief executive voiced the hope that even if its recurrent glioma project, Toca 511 & Toca FC, missed statistical significance in the Toca-5 trial, the data might still show a clinically meaningful effect and hence permit filing. In the event, the drug turned out to be worse than control, with overall survival being 11.1 months versus 12.2 months with standard of care (HR=1.06, p=0.6154). All the secondary endpoints were missed as well. This being Tocagen’s lead project and the only one to which the sellside had assigned sales forecasts, the company has been hit hard, with the 82% fall in its share price conferring a market cap of less than $19m, well below the company’s cash balance of $68m at the end of the second quarter. Tocagen promised various further examinations of the Toca-5 data, including molecular analyses and pre-planned subgroups, and will wait for these results before deciding whether to go ahead with the phase III trial in treatment-naïve glioblastoma patients that had been planned for this autumn. The real question, though, is how Toca 511 & Toca FC flunked so badly having previously survived two futility analyses.
Yesterday's green light for Axonics Modulation Technologies’ implanted sacral neuromodulator, r-SNM, for faecal incontinence is just the start for the product – the group expects a further US approval for urinary incontinence by the end of the year. The device stimulates the sacral nerves in the pelvic area, and is intended for patients who have failed on, or are unsuitable candidates for, drug therapy or other treatments. The device’s USP is that it can be recharged through the skin, which Axonics believes will allow it to carve out a niche from Medtronic. Medtronic’s Interstim devices, the first of which was approved in the US in 1997, is the main sacral nerve stimulator on the US market but cannot be recharged; when it runs out of juice it must be surgically removed and replaced. Axonics must make the most of this advantage: Medtronic plans to launch a rechargeable version of Interstim II in 2020. Neuromodulation devices continue to be approved or cleared by the FDA for a wide range of indications – the last two years have seen approvals for opioid withdrawal, heart failure and even cancer.
|Selected US neurostimulator approvals of the last two years|
|Device||Company||Type of stimulator||Indication||Date|
|r-SNM||Axonics Modulation Technologies||Sacral nerve stimulator||Faecal incontinence||Sep 9, 2019|
|Barostim Neo||CVRx||Carotid sinus nerve stimulator||Heart failure||Aug 16, 2019|
|IB-stim||Innovative Health Solutions||Non-implanted neurostimulator||Pain associated with IBS||Jun 7, 2019|
|NovoTTF-100L||Novocure||Low electric field tumour treatment||Cancer||May 23, 2019|
|Nerivio Migra||Theranica||Non-implanted neurostimulator||Migraine||May 20, 2019|
|Monarch||Neurosigma||Non-implanted neurostimulator||ADHD||Apr 19, 2019|
|Brainsway||Brainsway||Non-implanted neurostimulator||OCD||Aug 17, 2018|
|Cala One||Cala Health||Non-implanted neurostimulator||Upper limb tremor||Apr 26, 2018|
|TNM||Scion Neurostim||Non-implanted neurostimulator||Headache||Mar 26, 2018|
|Vercise||Boston Scientific||Deep brain stimulator||Parkinson’s symptoms||Dec 8, 2017|
|NSS-2||Innovative Health Solutions||Non-implanted neurostimulator||Opioid withdrawal||Nov 15, 2017|
|Source: EvaluateMedTech, company communications.|