Moderna Achieves COVID Case Number For 1st Interim Readout: What's Next

A late Wednesday announcement from Moderna Inc MRNA 5.34% signaled that the biopharma is still locked in a neck-to-neck race with Pfizer Inc. PFE 2.84% to develop a coronavirus vaccine.

What Happened: The number of COVID-19 cases required to conduct the pre-planned first interim analysis of Phase 3 data has accrued, the Cambridge, Massachusetts-based company said.

The Phase 3 COVE study is a large-scale, multicenter study of Moderna's investigational vaccine candidate RNA-1273.

The 30,000-strong study is evaluating a 100 mcg dose of the vaccine, with the primary endpoint being the prevention of symptomatic COVID-19 disease. Key secondary endpoints include prevention of severe COVID-19 disease and prevention of infection by SARS-CoV-2.

With a significant increase in the rate of case identification across the company's sites in the last week, the first interim analysis will include more than 53 cases, which Moderna said is the targeted trigger point for analysis. 

The company said data on these cases is being prepared for submission to the independent Data Safety Monitoring Board for analysis and recommendation. As of now, Moderna is blinded to whether the participants received the vaccine candidate or placebo.

What's Next: Given the achievement of the criteria for interim analysis, Moderna could release the interim readout anytime in the coming days. 

Stakeholders will likely make comparisons with Pfizer's data, which showed vaccine efficacy of over 90%.

Both the companies are developing a new class of mRNA vaccine  against the novel coronavirus, making comparisons inevitable.

The focus is also likely to rest on safety signals.

With the increase in COVID-19 infection rates, the sell-side sees scope for more than one company to operate profitably in the market. 

As for Pfizer, analysts model revenue between $4.6 billion to $7.2 billion in 2021.

https://www.benzinga.com/general/biotech/20/11/18342060/moderna-achieves-covid-19-case-number-for-first-interim-readout-whats-next

Pfizer's tafamidis extends survival in patients with rare heart failure condition

• Following up on its initial announcement in March 2018, Pfizer (PFE -2.5%) releases additional data from a Phase 3 clinical trial, ATTR-ACT, evaluating Vyndaqel (tafamidis meglumine) 80mg/Vyndamax (tafamidis) 61 mg in patients with a subtype of transthyretin amyloidosis (ATTR) called ATTR cardiomyopathy (ATTR-CM).
• Per the first report, the study met the primary endpoint demonstrating a statistically significant reduction in the combination all-cause mortality and frequency of cardiovascular (CV)-related hospitalizations at month 30 compared to placebo. The relative risk reductions in all-cause mortality and CV-related hospitalizations were 30% and 32%, respectively.
• A long-term extension study is ongoing with an estimated completion date in December 2026.
• The FDA approved the transthyretin stabilizer in May 2019 for ATTR-CM.
• https://seekingalpha.com/news/3635634-pfizers-tafamidis-extends-survival-in-patients-rare-heart-failure-condition
  

Lockdown chatter puts chill on rate rally, hits bank prices

• Threatening over the last few days to jump above 1% for the first time since the March panic, the 10-year Treasury yield has pulled back eight basis points today to 0.90%.
• The iShares 20+ Year Treasury Bond ETF (NASDAQ:TLT) is ahead 1%, and the ProShares UltraShort 20+ Year Treasury ETF (NYSEARCA:TBT) is down 1.9%. The financial sector is the worst performer in the S&P today, the XLF down 1.4%. The SPDR S&P Regional Banking ETF (KRE -1.8%). Individual players: Bank of America (BAC -2.8%), JPMorgan (JPM -1.8%), Citigroup (C -1.7%).
• Euphoria around a vaccine is what had sent the 10-year yield surging earlier this week, but the last 24-48 hours have seen renewed coronavirus-related restrictions put in place in New York, New Jersey, and Ohio, among other U.S. locales, not to mention the continued spread of lockdowns in Europe.
• Last night, the University of Minnesota's Michael Osterholm suggested a national lockdown of four-six weeks might be necessary to stop the virus. Osterholm has been whistling a similar tune for months (including teaming up with the Fed's Neel Kashkari in August), but now he's among those running policy for the incoming Biden administration, so his trial balloon is worth paying some attention to.
• https://seekingalpha.com/news/3635610-lots-of-lockdown-chatter-puts-chill-on-rate-rally-hits-bank-prices
  

Five Prime looks to turn a corner

With Five Prime’s stock surging 300% overnight the company will be hoping to put a disastrous three years behind it. The reason for the sudden enthusiasm lies in survival data with bemarituzumab, a wholly owned asset the group had touted last year, but which until now had little to back up the hype.

The findings, in the Fight trial in first-line stomach cancer, position the company’s lead project as the first mover in a new approach, FGFR2B inhibition, with little competition. Of course they come with caveats, and the stock move has to be seen in the context of a share price that had lost 90% of its value since 2016.

The collapse in 2016/17 was triggered by disappointing data with cabiralizumab, an anti-CSF-1R MAb partnered with Bristol Myers Squibb. A restructuring and C-suite sweep-out followed (Five Prime moves towards subprime, January 16, 2019). Five Prime’s phoenix-like rise sees it valued at $800m, which by today’s standards seems undemanding.

Taking the Fight

The spotlight now falls on bemarituzumab. Fight was the first large trial in front-line gastric/gastroesophageal junction cancer to screen for FGFR2B overexpression, which the company says accounts for 30% of non-Her2-driven cancers of this type; according to last year’s investor pitch this amounts to 56,870 addressable patients.

Fight combined bemarituzumab with chemo, and compared its progression-free survival versus chemo alone as primary endpoint; overall survival was a secondary measure. Both showed a statistically significant effect, according to the study’s design, with median PFS improving 2.1 months to 9.5 months, and median OS not yet reached but showing a 42% reduction in risk of death.

This is where the caveats begin, however. Five Prime revealed that the p value threshold for this trial was 0.2, and according to this both measures succeeded, with p=0.073 and 0.027 respectively. Had Fight used the more common definition of statistical significance of 0.05 the study would have been a bust, since its primary endpoint would have missed this stricter threshold.

The group defended its design, saying this was not uncommon for a small phase II study; it said it had not designed Fight as a registrational study, and had only been hoping to see a survival trend. As such, the seemingly positive data appear to have come as a big surprise.

Questions

If Five Prime now seeks to raise cash, potential investors will question why the upper bound of the confidence interval for PFS is above 1.0, and why 34% of bemarituzumab subjects discontinued because of an adverse event versus just 5% in the control group. And nothing has been said about baseline patient characteristics, an imbalance in which could account for the apparent benefit.

A further spanner in the works is that the front-line setting is set to change, with Merck & Co and Bristol both recently claiming successes with anti-PD-1 antibodies, though histology and biomarkers complicated data interpretation (Esmo 2020 – double win complicates the gastric cancer picture, September 21, 2020).

If FGFR2B is indeed implicated in gastric cancer competing companies should take note. EvaluatePharma data reveal several with assets against this target, though apparently none with specificity at the 2B subtype. While bemarituzumab is an antibody most are small molecules; Incyte’s Pemazyre, which hits FGFR1/2/3, is marketed for cholangiocarcinoma.

Five Prime also claims that FGFR2B is overexpressed in subgroups of squamous NSCLC, triple-negative breast, ovarian and pancreatic cancers. For now, however, its focus must be on designing a phase III gastric cancer study with a primary endpoint of OS.

Selected clinical assets with activity at FGFR2
Project	Company	Target	Type
Marketed
Pemazyre	Incyte	FGFR1, 2 & 3	Small molecule
Phase II
E7090	Eisai	FGFR1, 2 & 3	Small molecule
Debio 1347	Debiopharm/Roche	FGFR1, 2 & 3	Small molecule
HMPL-453	Hutchison China Meditech	FGFR1, 2 & 3	Small molecule
ABSK091	Abbisko Therapeutics	FGFR1, 2 & 3	Small molecule
Bemarituzumab	Five Prime/Zai Lab	FGFR2B	Antibody
Phase I
3D-185	3D Medicines	FGFR1, 2 & 3, CSF1R	Small molecule
DS-1123	Daiichi Sankyo	FGFR2	Antibody
RLY-4008	Relay Therapeutics	FGFR2	Small molecule
PRN1371	Sanofi (ex Principia)	FGFR1, 2, 3 & 4	Small molecule
Source: EvaluatePharma & company statements. https://www.evaluate.com/vantage/articles/news/trial-results/five-prime-looks-turn-corner

Qiagen enters the T-cell testing fray

Detecting a T cell-mediated immune response might be the next frontier in Covid-19 testing. Qiagen, which already makes tests for the coronavirus’s RNA and antigens as well as for antibodies produced by Covid-19 patients, has just cut a deal to move into T-cell testing too. 

The Dutch group has signed up Tscan Therapeutics, a biotech currently focused on oncology, to help it develop an assay for coronavirus-reactive T cells. The success of Qiagen’s Covid-19 testing business gave the group the courage to opt out of being acquired by Thermo Fisher Scientific, but it needs to keep on top of new innovations. So far, however, Qiagen is some way behind groups including Oxford Immunotec and Adaptive Biotechnologies in the T-cell testing space. 

It is believed that a T-cell immune response to Covid-19 might provide longer-term protection against reinfection with the virus than antibodies, kicking in earlier and lasting longer. Detecting responsive T cells could provide a more reliable way to determine exposure to the coronavirus and, if a link to some level of immunity can be proven, perhaps allow at least some people to return to normal life. 

Tscan’s technology is currently geared towards engineering T cells to recognise and kill cancer cells. Qiagen has taken an option to several of Tscan’s immunodominant T-cell targets, associated sequences and other data to help with the development of in vitro diagnostic tests. Before exercising this option, Qiagen has the right to further evaluate Tscan’s discoveries. Terms of the deal were not disclosed.

Immunodominance refers to the ability of some viral antigens or epitopes to induce a meaningful immune response, where others do not. The immunodominant targets Qiagen has licensed were identified by Tscan’s TCR/Target discovery platform, which mapped the specific epitopes in Sars-Cov-2 that are recognised by the CD8+ T cells of patients recovering from Covid-19. 

Detect and discover

It is not clear how long it might take Qiagen to turn this technology into a working test for Covid-19 exposure. What is apparent is that the company is behind at least two others in this space. 

This week data emerged on Oxford Immunotec’s T-Spot Discovery Sars-CoV-2 test, making a tentative link between a T-cell response and resistance to reinfection with the virus (First data hint at T-cell immunity to Covid-19, November 10, 2020). And a study of a T-cell test developed by Adaptive Biotechnologies has also been detailed in a preprint. 

Adaptive conducted a 100-patient head-to-head study comparing its T-Detect Covid test with two antibody tests – Roche’s Elecsys Anti-Sars-Cov-2, which tests for both IgG and IgM, and Labcorp’s Sars-Cov-2 Antibody IgG test. The tests were set at 99.8% specificity to minimise false positives. In this study, 94% of patients were detected as positive by Adaptive’s T-cell test versus 90% for Roche’s and 87% for Labcorp’s respectively.

In a different study, performed in collaboration with the University of Padua in Italy, which has not been published but was toplined during Adaptive’s third-quarter call on Tuesday, T-Detect Covid identified 97% of PCR-confirmed past infections, while an antibody test from Diasorin identified only 77%. 

Adaptive intends to submit these data to the FDA to support emergency use authorisation for T-Detect. Oxford Immunotec is cagey about its regulatory plans, but if Adaptive can get an EUA for a T-cell test then in principle there is nothing barring the way for T-Spot Discovery. Qiagen might have to get its skates on.

Source: Adaptive Biotechnologies’ Q3 results presentation.

https://www.evaluate.com/vantage/articles/news/deals/qiagen-enters-t-cell-testing-fray