Target to $85 from $90
Wednesday, January 19, 2022
3 doses of Valneva's COVID-19 Vaccine Neutralizes Omicron
Valneva SE (NASDAQ: VALN) has announced results from an initial laboratory study demonstrating that serum antibodies induced by three doses of Valneva's COVID-19 vaccine candidate, VLA2001, neutralize the omicron variant.
Sera from 30 participants in the Phase 1/2 trial VLA2001-201 were used to analyze the neutralization of the ancestral SARS-CoV-2 virus and the Delta and Omicron variants.
All 30 samples presented neutralizing antibodies against the ancestral virus and Delta variant, and 26 samples (87%) presented neutralizing antibodies against the Omicron variant.
The mean fold reduction of neutralization relative to the ancestral virus was 2.7-fold for Delta and 16.7-fold for Omicron.
The Company continues to expect to complete regulatory submissions in Europe, the U.K., and Bahrain in time to receive potential regulatory approvals in Q1 of 2022.
Valneva's whole virus inactivated COVID-19 vaccine candidate uses Dynavax Technologies Corporation's (NASDAQ: DVAX) adjuvant.
What mental health apps actually work? Analysis finds data is sparse
Researchers at the University of Wisconsin-Madison have spent years making sure that their meditation app, called the Healthy Minds Program, passes clinical muster and delivers positive outcomes. Designing studies to test the app’s efficacy led Simon Goldberg, an assistant professor at UW, to confront the mountain of thousands of studies of different mobile mental health tools, including apps, text-message based support, and other interventions.
Researchers had taken the time to synthesize some of the studies, but it was hard, even for someone steeped in the science like Goldberg, to draw definitive conclusions about what works and what doesn’t. So Goldberg teamed up with a few other researchers and took a step back to see if they could put order to the work collected in these meta-analyses — a kind of deep meditation on the existing research inspired by UW’s meditation app.
The meta-review, published on Tuesday in PLOS Digital Health, examined 14 meta-analyses that focused specifically on randomized control trials for mental health interventions, including treatments for depression, anxiety, and smoking cessation. In total, the review included 145 trials that enrolled nearly 50,000 patients. The review found universal shortcomings in study design, leading the researchers to write that they “failed to find convincing evidence in support of any mobile phone-based intervention on any outcome.”
It’s a provocative claim that hints at the work ahead for an industry garnering billions of dollars in investment to develop products that can help people more easily manage health conditions from their phones. Researchers and entrepreneurs are hoping to collect enough evidence to prove to health care policymakers and the public that their interventions work.
But it’s also a sign of how nascent the industry still is, and how even scientists and companies committed to rigorous evaluation are still sorting out what a good trial of an app looks like. Goldberg told STAT that though the evidence isn’t strong yet, better studies will surely emerge for some of the more promising interventions.
“I would bet the farm that if you wait five years and people keep running these trials, there will be convincing evidence,” he said.
To analyze the pool of studies, the researchers identified 34 different combinations of study criteria: the population targeted, the type of intervention, the control, and the outcome sought. The researchers gathered the effect sizes for these studies and then graded the evidence based on the number of factors, like the statistical significance of the results and the consistency of findings across studies.
That none of the interventions managed to show “convincing evidence” reflects that they weren’t able to satisfy a high standard, including an absence of publication bias, or the tendency to publish only favorable results, which was rarely assessed.
Eight of the interventions, however, were found to hit a slightly lower bar of having “highly suggestive” evidence — though that came with the caveat that the effect of the interventions and the strength of the evidence both “tended to diminish as comparison conditions became more rigorous,” the authors wrote.
None of those eight used control treatments that were designed to be therapeutic. Only one type of treatment, text message support for smoking cessation, was compared to an active control, meaning the comparison group received something to occupy their time and attention.
“For me, this suggests that mobile phone-based interventions might not be uniquely effective, but still are effective relative to nothing or non-therapeutic interventions,” said Goldberg. “Given the scalability of these interventions, that’s still good news.”
Rajani Sadasivam, a professor at the University of Massachusetts Chan Medical School who develops text-based services to help people quit smoking, agreed that researchers need to consider cost and reach. For example, a face-to-face, 45-minute counseling session to help someone quit smoking would almost certainly work better than a text-based intervention, but the text-based intervention will be easier for far more people to access.
Lisa Marsch, the director of the Dartmouth Center for Technology and Behavioral Health, told STAT that the new meta-review highlights the limitations of existing literature, including that researchers often don’t dig into variables that can impact outcomes and rarely reported adverse effects.
She said one of the downsides is that meta-analyses tend to group together interventions that may be quite different from each other, like a mobile app that delivers a “potent therapeutic approach” like cognitive behavioral therapy and another that provides inspirational messages or tips. Each might have different levels of clinical impact.
“Lumping them together into categories such as smartphone apps or text messaging apps loses sight of this,” she said. “This is quite distinct from something like a medication which… is more invariable across trials.” Another limitation of the study, as noted by Goldberg and colleagues, is that the paper leaves out evidence that hadn’t been examined in past meta-analyses.
Despite the somewhat dismal conclusions about convincing evidence and active controls, Goldberg sees the study’s findings as a positive sign of where the research is headed.
“Given how recent apps are in human history, there’s a ton of research on them, and there’s evidence that they’re yielding benefits,” he said. “To me, it’s super encouraging.”
https://www.statnews.com/2022/01/19/mental-health-meditation-app-evidence/
Asco-GI 2022 – Cardiff’s data weaken, but pivotal plans are afoot
Cardiff Oncology's attempt to hit all subtypes of Kras-mutated colorectal cancer with its PLK1 inhibitor onvansertib is being tested in an ongoing second-line study, but the latest data cut makes for disappointing reading. Responses waned on last year, in confirmed and unconfirmed analyses alike. The company's massaging of the numbers also failed to impress investors, with the stock plunging 23% in early trade. A patient who improved from stable disease to an unconfirmed partial response after data cutoff was included in results presented to analysts last night, a PR that will not feature in a poster due to be presented at Asco-GI this weekend. Cardiff execs stressed that the data remained stronger than the “proof-of-concept” criteria set for this trial. This called for ORR of 20% and median PFS of at least six months – mPFS currently sits at 9.4 months, though this is an interim finding. They also pointed to responses across several subtypes of Kras mutation. Cardiff plans to move into phase 3 later this year, and Pfizer has first pass at any data as part of an equity investment made last year, but jittery biotech investors have clearly seen enough to fret about for now.
| Onvansertib in Kras-mutant colorectal cancer: the evolving data from a phase 1/2 dose finding study | |||
|---|---|---|---|
| Announced | Data cutoff | Responses (ORR) | Confirmed responses (ORR) |
| 28 Apr 2020 (AACR) | 24 Jan 2020 | 3/8 PR (38%) | Unclear |
| 17 Sep 2020 (Esmo) | 4 May 2020 | 5/11 PR (45%) | 4/11 PR (36%) |
| 15 Jan 2021 (Asco-GI) | 1 Nov 2020 | 5/12 PR (42%) | 4/12 PR (33%) |
| 12 Apr 2021 | Unclear | 7/18 PR (39%) | 4/18 PR (22%) |
| 8 Sep 2021 | 2 Jul 2021 | 12/32 PR (38%) | 10/32 PR (31%) |
| 2 Jul 2021 at RP2D | 8/19 PR (42%) | 7/19 PR (37%) | |
| 18 Jan 2022 (Asco-GI) | 3 Dec 2021* | 17/48; 1 CR, others PR (35%)* | 13/48; 1 CR, others PR (27%) |
| 3 Dec 2021 at RP2D* | 12/35; 1 CR, others PR (34%)* | 10/35; 1 CR, others PR (29%) | |
| RP2D=recommended phase 2 dose. *Data as presented by the company, including a patient who achieved a PR (from SD) after cutoff; data on the poster due to be presented at Asco-GI will not include this PR, so ORR will be lower. Source: company statements. | |||
Source: Cardiff Oncology company presentation.
Cytokinetics hopes to resurrect omecamtiv
Remember omecamtiv mecarbil? It might be back. The Cytokinetics heart failure project, whose technically successful Galactic-HF study was nevertheless bad enough for Amgen to pull the plug on a licensing deal, could soon be reviewed by the FDA.
Remarkably, however, Cytokinetics will not say whether omecamtiv has been filed, though its strategy is clear: to position the cardiac myosin stimulant at the severe end of heart failure, where it claims the effect in Galactic-HF was strongest. Within the next two weeks investors will be reminded of this project again when a second phase 3 trial, Meteoric-HF, yields topline data.
That said, Meteoric-HF is not central to omecamtiv’s filing, Cytokinetics stressed at its recent presentation at the JP Morgan healthcare conference. Rather, the trial, testing omecamtiv’s effect on exercise tolerance, could be supplemental, and Mizuho analysts reckon it could ultimately expand the drug’s commercial opportunity by 10-20%.
Galactic
That opportunity now hinges on Galactic-HF, a heart failure trial in which, back in October 2020, omecamtiv failed to improve cardiovascular death, a key secondary endpoint in which Astrazeneca’s Farxiga has shown a benefit.
Galactic-HF did technically hit its primary endpoint, a composite of death or heart failure events, but the 8% risk reduction (p=0.0252) seriously underperformed Farxiga’s 26%. Cytokinetics’ share price plunged, and the result was sufficiently underwhelming for Amgen to hand back rights the following month.
But at subsequent medical meetings Cytokinetics has banged the table regarding a subgroup of patients with severe heart failure, in whom it says Galactic-HF demonstrated a more convincing 20% reduction in death or heart failure events. This subgroup comprises patients with NYHA level III-IV and ejection fraction at or below 30%.
This subgroup is said to have driven the benefit in Galactic-HF overall, and the post hoc analysis is backed by the fact that in patients who did not meet these criteria omecamtiv had virtually no effect.
Subgroup analysis of Galactic-HF. Source: Cytokinetics.
This might have been a post hoc data dredge, but investors seem to have bought into the story. Since October 2020 Cytokinetics shares have more than doubled, though this will also have been down to success with aficamten (CK-274), a separate project.
Cytokinetics has sold a small royalty on both assets to Royalty Pharma in two separate transactions, of which the one on aficamten, signed two weeks ago, was done specifically to fund omecamtiv's potential commercialisation.
The proof of the enthusiasm lies in regulatory interactions, though Cytokinetics remains guarded over whether omecamtiv has even been filed. The group had targeted filing by 2021 year end, but decided not to reveal anything until the submission was accepted or rejected. “As the FDA has up to 60 days to communicate back to us we'll be communicating the status of that NDA hopefully soon,” Robert Blum, its chief executive, told JP Morgan.
Meteoric
Meanwhile, the Meteoric-HF trial assesses how omecamtiv might improve exercise capacity in heart failure patients, specifically looking at change in peak VO2 on cardiopulmonary exercise testing from baseline to week 20, versus placebo.
Peak VO2 measures the amount of oxygen that can be delivered to tissues, and Meteoric-HF enrolled patients described as quite severely depressed in terms of oxygen delivery, specifically with peak VO2 of less than 75% of normal. Cytokinetics says the study is powered to show relatively small increases, but investors should focus on clinical relevance rather than mere statistical significance.
Cytokinetics says omecamtiv probably needs to show at least a 1ml/kg/min increase from baseline in peak VO2 – adjusted for placebo – to be clinically meaningful. Much will therefore hinge on how the placebo recipients perform.
The best case has omecamtiv approved this year, with a positive Meteoric-HF readout leading to a supplemental NDA filing to expand its label. Should such an admittedly low-probability scenario come about Amgen will rue the day it gave up on omecamtiv.
https://www.evaluate.com/vantage/articles/news/trial-results/cytokinetics-hopes-resurrect-omecamtiv
Asco-GI 2022 – Seagen keeps the faith in souped-up CD40 agonism
Do not write off CD40. Stimulating this target for oncology use has proved difficult, but companies are not giving up, though many have accepted that something more than a simple agonist approach might be needed. Seagen’s SEA-CD40 is a nonfucosylated CD40 agonist MAb, and phase 1 data just unveiled at the Asco-GI meeting show 44% overall response across two doses in 61 evaluable patients in a first-line pancreatic ductal adenocarcinoma cohort; median PFS and OS are 7.4 and 15.0 months respectively. It is difficult to parse SEA-CD40’s contribution, as the project was combined with Keytruda, Abraxane and gemcitabine, but Abraxane’s label cites ORR, mPFS and mOS of 23%, 5.5 months and 8.5 months, respectively, in combination with gemcitabine. SEA-CD40 recently moved into phase 2, as did Celldex’s fully human agonist CDX-1140, while new clinical entrants since Evaluate Vantage last analysed the CD40 field include Abbvie’s ABBV-927, Biontech/Genmab's GEN1042, Lyvgen’s LVGN7409 and Shattuck’s SL-172154. Discontinuations include ABBV-428 and Astrazeneca’s MEDI5083, while Roche recently canned selicrelumab in favour of RG6189, a bispecific that induces CD40 stimulation solely in the presence of FAPα and is now in a phase 1 Tecentriq combo trial.
| Selected clinical assets targeting CD40 in cancer | |||
|---|---|---|---|
| Project | Company | Mechanism | Clinical trial |
| Phase 2 | |||
| APX005M/ sotigalimab | Apexigen | CD40 agonist MAb | Melanoma and oesophageal/GEJ |
| CDX-1140 | Celldex Therapeutics | Fully human CD40 agonist MAb | Pancreatic cancer |
| SEA-CD40 | Seagen | Nonfucosylated CD40 agonist MAb | Combo trial |
| ABBV-927 | Abbvie | CD40 agonist MAb | Pancreatic cancer |
| YH003 | Eucure (Biocytogen) | Humanised CD40 agonist MAb | Toripalimab combo |
| Phase 1/2 | |||
| Mitazalimab/ ADC-1013 | Alligator Bioscience | CD40 agonist MAb; J&J terminated deal Jul 2019 | Pancreatic cancer |
| GEN1042 | Biontech/Genmab | CD40 & 4-1BB Duobody | Solid tumours |
| Phase 1 | |||
| FAP-CD40/ RO7300490 | Roche | FAPα-dependent CD40 agonist bispecific | Tecentriq combo |
| LVGN7409 | Lyvgen Biopharma | CD40 agonist MAb | MonoRx & combo |
| SL-172154 | Shattuck Labs | CD40L-SIRPα fusion protein | Ovarian and head & neck cancers |
| Source: Evaluate Pharma. Note: excludes non-oncology applications and CD40-blocking approaches for autoimmune diseases. https://www.evaluate.com/vantage/articles/events/conferences-snippets/asco-gi-2022-seagen-keeps-faith-souped-cd40-agonism | |||
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