Study of Abivax COVID-19 drug expanded to Brazil

French biotech Abivax SA (OTCPK:AAVXF) announces that Brazil’s Health Regulatory Agency has signed off on its Phase 2/3 clinical trial, MiR-AGE, evaluating lead candidate ABX464 for the treatment of inflammation and prevention of acute respiratory failure in COVID-19 patients.

The study was previously OK’d in France and Germany.

The primary endpoint is the proportion of patients with no invasive or non-invasive mechanical ventilation (excluding supplemental oxygen) and who are alive at the end of the 28-day treatment period.

The estimated primary completion date is December.

ABX464 is an orally available small molecule that, it says, exhibits an antiviral effect, an anti-inflammatory effect and tissue repair properties preventing longer-term pulmonary problems.

https://seekingalpha.com/news/3585125-study-of-abivax-covidminus-19-drug-expanded-to-brazil

Cipla launches COVID-19 drug remdesivir in India as disease takes hold

Efforts to get Gilead’s experimental COVID-19 drug remdesivir to patients in badly-hit India are building after drug maker Cipla announced it had launched the drug in the country. 
The launch follows an agreement in May where Gilead extended to a voluntary non-exclusive licence to Cipla to manufacture and market a generic version of remdesivir.
The Drug Controller General of India has granted Cipla regulatory approval for restricted emergency use as part of a fast-track process, using the brand name Cipremi. 
This includes a risk management plan for use of the drug, including patient consent documents, post-marketing surveillance and a phase IV trial in the country. 
In May, Gilead signed non-exclusive voluntary licensing agreements with six Indian pharmaceutical companies to boots the supply of remdesivir. 
These companies were Dr Reddy’s Laboratories, Zydus Cadila, Biocon, Hetero Labs, Jubilant Lifesciences, and Cipla. 
Remdesivir was the first drug to show meaningful clinical activity against COVID-19 in a phase 3 trial, reducing the time to recovery in patients hospitalised with the disease. 
It also showed a numerical trend towards reducing mortality rates and has also been approved by the FDA under an Emergency Use Authorisation. 
Cipla said that it will supply through government and open market channels to ensure fair distribution. 
India has become one of the countries worst hit by the disease and recorded 15,413 new cases on Sunday and more than 14,000 cases so far today. 
The country’s death toll from the disease is approaching 14,000 and it reported 445 new deaths today. 
The disease has become concentrated in hotspots in the country’s poorest districts and the outbreak is centred in the states of Delhi, Maharashtra and Tamil Nadu. 
Remdesivir has competition as a treatment for COVID-19 – a UK clinical trial has shown the cheap steroid dexamethasone can reduce mortality and recovery times in patients hospitalised with the disease. 

Cipla launches COVID-19 drug remdesivir in India as disease takes hold

Third-quarter events to watch for large drug makers

Biogen’s aducanumab filing is keenly awaited, as are clinical data from Sanofi, Bristol Myers Squibb, Lilly and others.

As the second quarter comes to a close Evaluate Vantage delves into non-Covid-19-related catalysts due next quarter for large drug makers. One of the most keenly awaited events is not clinical data but a filing for Biogen’s Alzheimer’s projecr aducanumab. Biogen had previously guided to a submission earlier in the year, but a delay announced in April saw shares fall over 9%.
The submission will be based on the Emerge and Engage studies whose reanalysis claimed to have teased out an efficacy signal if dosing was high enough for long enough. An advisory committee will no doubt be called, to scrutinise the statistical rigour of the analysis and aducanumab’s toxicity profile, although first the FDA must accept the filing.
Just last week Biogen lost a patent dispute with Mylan over its multiple sclerosis drug Tecfidera, making it even more reliant on aducanumab.
The company, which has been criticised for its thin pipeline, also expects a readout on a mid-stage Parkinson’s candidate in the second half. BIIB054, an anti-alpha synuclein MAb, is in the phase II Spark study whose primary measure is safety. Key secondary measures are geared towards the pharmacodynamic effects of BIIB054 on dopaminergic nerves, as well as pharmacokinetics and immunogenicity.
Another anti-alpha synuclein MAb, Roche/Prothena’s prasinezumab, has previously reported mixed results. The ongoing phase II Pasadena study failed to meet the primary endpoint of change in MDS-UPDRS after 52 weeks, but did show signs of efficacy in secondary and exploratory endpoints looking at cognitive and other markers of disease. The 52-week blinded extension is ongoing.
Oncology
A test of Sanofi’s $2.3bn Synthorx acquisition is expected in the second half of the year, with data from Thor-707 in the phase I/II Hammer trial. As a non-alpha IL-2, Thor-707 should avoid triggering vascular leak syndrome, a serious side effect that has been attached to IL-2 therapies, and the Hammer study primarily looks at toxicities.
Thor-707 is being investigated as a single agent and in combination with an unspecified PD-(L)1 agent in solid tumours; a combination with Sanofi’s own Libtayo is likely. Libtayo was approved in 2018, making it a late entrant to a very competitive market, so a combination with Thor-707 could differentiate it. Combining IL-2 treatment with PD-(L)1 inhibition is thought to enhance CD8+ T-cell responses, giving greater antitumour effects than checkpoint blockade alone.
In first-line liver cancer Astrazeneca’s Himalaya trial is expected to report soon. The study tests Imfinzi as a monotherapy, or in two combinations with the anti-CTLA-4 agent tremelimumab, against Nexavar; the primary outcome is overall survival.
Earlier this month the first immunotherapy was approved in a front-line liver cancer setting − Roche’s Tecentriq/Avastin combo, backed by the Imbrave-150 study. The combination reduced risk of death by 42% (p=0.0006) and cut risk of disease worsening or death by 41% (p<0.0001) versus Nexavar.
Fibrosis
Bristol Myers Squibb’s turn in Nash is with the FGF21 stimulant pegbelfermin. The phase IIb Falcon 1 study could report in the second half, while a second, longer-term study has a primary completion date in September.
Falcon 1 is testing three doses and is a 24-week trial. The primary endpoints include ≥1 stage improvement in fibrosis without worsening of Nash, and Nash improvement with no worsening of fibrosis as determined by liver biopsy. Fibrosis and activity scores are two further primary measures.
In a phase IIa study once-weekly pegbelfermin at 20mg reduced hepatic fat fraction by a placebo-adjusted 3.9 percentage points (p=0·008).
Akero is developing a similar agent, AKR-001, and in April reported impressive MRI data. The relative reductions in liver fat were 63% to 72% versus baseline for the three AKR-001 doses tested. Biopsy data were pegged for the second quarter, so could come any day now.
The table below shows additional third-quarter events for large drug makers. A look at catalysts for smaller companies will be published in the coming days.

Selected Q3 clinical catalysts (excludes Covid-19 data)
Project	Company	Therapy area	2026e indication sales ($m)	Q3 event	Evaluate Vantage note/story link
Aducanumab	Biogen/Eisai	Alzheimer’s disease	2,987	Expected to complete filing in Q3, based on Engage and Emerge data	See text
Ide-cel	Bristol Myers Squibb/Bluebird	Multiple myeloma	1,452	Filing will be resubmitted by the end of July (part of the Celgene CVR)	RTF letter received in May (Another knock for the Celgene contingent value right)
Yescarta	Gilead	Diiffuse large B-cell lymphoma	1,331	Zuma-7, versus SOC, data H2	Seeks to expand Yescarta’s lymphoma use from third to second line
Bimekizumab	UCB	Psoriasis	947	Be Radiant phase III head-to-head vs Cosentyx	UCB’s growth driver squares up against the competition
Imfinzi + tremelimumab	Astrazeneca	1L liver cancer	124	Himalaya, H2	See text
BIIB054 (cinpanemab)	Biogen	Parkinson’s disease	26	Phase II Spark, H2	See text
Thor-707	Sanofi	Solid tumours	11	PhI/II Hammer, H2	See text
Pegbelfermin	Bristol Myers Squibb/Ambrx	Nash	7	Falcon 1 study, primary completion was April (Falcon 2 primary completion September)	See text
Mevidalen/LY3154207 (D1 PAM)	Lilly	Lewy Body Dementia	5	Phase II Presence, primary completion July	Dopamine D1 positive allosteric modulator, 340 patient trial with three doses vs placebo
EvaluatePharma sales by indication data. Source: company releases, analyst notes & clinicaltrials.gov.

https://www.evaluate.com/vantage/articles/events/company-events/third-quarter-events-watch-large-drug-makers

AACR 2020 – Biontech and Roche try to resuscitate cancer vaccines

A first-in-human study of the companies’ neoantigen mRNA cancer vaccine fails to rewrite these agents’ poor history.

It is surely a measure of cancer vaccines’ abysmal track record that a mere 7% overall response rate is enough for a spotlight at an oncology conference. Step forward RO7198457, a personalised neoantigen vaccine in development by Roche and Biontech, the first human data on which have just been unveiled at this year’s second virtual AACR meeting.
However, despite being highlighted at a pre-meeting press conference, results of a phase I multi-tumour study have shown RO7198457 plus Tecentriq to have “modest activity in the heavily pretreated dose-escalation patient population”, admitted Dr Juanita Lopez of Royal Marsden NHS Foundation trust. Some investors will come away wanting to have seen better.
But Dr Lopez insisted that the trial had at least one important aspect, saying: “The thing I’m most excited about is that we’ve managed to show that in the majority of patients we were able to elicit a specific immune response.” It is more typical for an immune response to fail to be initiated, as evidenced by no immune cells being seen within the tumour.
In the trial’s Tecentriq combo cohort neoantigen-specific T-cell responses induced by the vaccine were observed in 46 of 63 subjects. In a RO7198457 monotherapy cohort, detailed in a separate AACR presentation, T-cell responses were observed in the peripheral blood of 14 of 16 patients.
Not sufficient?
However, Dr Lopez accepted that “this in itself may not be sufficient”.
RO7198457 monotherapy yielded just one, complete, response in 26 evaluable subjects, while in combo with Tecentriq there were eight partial and one complete remission in 108 evaluable patients. One reason for the poor efficacy suggested by Dr Lopez was that subjects had been heavily pretreated, with a median three prior therapies.
It is not at all clear how many subjects might have responded with Tecentriq alone, and Dr Lopez would not indulge in cross-trial comparisons. 39% of the patients entering the combo cohort had failed immunotherapy, but she would not say what the percentage was for the nine responders.
Dr Lopez did detail two remissions, one partial, one complete, in an initial dose escalation: the first was checkpoint-experienced and PD-L1-high, but the second was neither. Further data will be presented on Tuesday.

Source: Dr Juanita Lopez & AACR.

RO7198457, also known under the codes RG6180 and BNT122, is the first project to emerge from a deal Roche and Biontech had struck back in 2016. This, of course, was before Biontech floated and was able to bask in its current $11bn valuation, which is largely the result of its efforts to develop an mRNA vaccine against Covid-19.
Two clinical trials of RO7198457 are now under way: the phase I dose-escalation study just unveiled at AACR, and a phase II trial called Imcode-001, in combination with Merck & Co’s Keytruda in front-line melanoma, which started a year ago. The companies also plan two randomised studies in resected lung and colorectal tumours.
Conceptually RO7198457 is anything but simple, having to be manufactured on a per-patient basis. Each patient’s tumour is analysed and sequenced to identify about 20 neoantigens, for which corresponding mRNA is generated and encapsulated in a liposome that is then injected with the aim of eliciting an immune response.
It is promising that evidence of the mechanistic rationale for such an approach has been shown. But, unless T-cell responses translate into clinical remissions, cancer vaccines will not have a future.
https://www.evaluate.com/vantage/articles/events/conferences/aacr-2020-biontech-and-roche-try-resuscitate-cancer-vaccines

BeiGene/SpringWorks doublet therapy encouraging in preclinical studies

BeiGene (BGNE -1.2%) and SpringWorks Therapeutics (SWTX +1.5%) announce positive preclinical data on the combination of the former’s RAF dimer inhibitor lifirafenib and the latter’s MEK inhibitor mirdametinib, currently in Phase 1b/2 development for the treatment of advanced/refractory solid tumors harboring MAPK pathway mutations, including RAS. The results were presented virtually at the American Association for Cancer Research Annual Meeting.

Across a panel of RAS-mutated cancer models, clinically relevant concentrations of the drugs showed potent and synergistic activity. In two xenograft models (tissue transplanted from one species to another) the combo showed synergy as measured by pharmacodynamic pathway inhibition and tumor regression.

The dose-escalation portion of the Phase 1b/2 trial should be completed by year-end. Dose-expansion cohorts, including patients with KRAS-positive non-small cell lung cancer and KRAS-positive endometrial cancer, will follow. Preliminary data should be presented at a medical conference in 2021.

https://seekingalpha.com/news/3584970-beigene-springworks-doublet-therapy-shows-encouraging-action-in-preclinical-studies

Aridis’s AR-501 shows positive effect in early-stage study

Aridis Pharmaceuticals’s (ARDS -3.0%) AR-501 aerosols demonstrated to be well tolerated, with no serious adverse events, in phase 1 portion of Phase1/2a trial.

AR-501, an inhaled formulation of gallium citrate is under  development for chronic lung infections in patients with cystic fibrosis (“CF”), as a once-per-week dosing for self administration.

Transient incremental changes in airflow as measured by spirometry were observed in both AR-501 and placebo recipients that were not dose related.

All adverse events were Grade 1 or Grade 2, and mostly respiratory that were balanced between AR-501 and placebo recipients.

AR-501 Phase 2a received recommendations from Data Safety Monitoring Board (“DSMB”) and Safety Monitoring Committee (“SMC”), to proceed at all doses in adult subjects with CF.

Phase 2a results are expected in 2H 2021.

https://seekingalpha.com/news/3584973-aridiss-arminus-501-shows-positive-effect-in-early-stage-study

Gilead to launch study of inhaled formulation of remdesivir

In an open letter, Gilead Sciences (GILD -2.5%) Chairman & CEO Daniel O’Day says the company will launch a Phase 1 clinical trial this week evaluating an inhalable version of remdesivir in healthy volunteers. The formulation, administered via nebulizer, could potentially allow use outside of the hospital for the treatment of earlier stages of COVID-19.

The formulation that the FDA approved for emergency use for severely ill COVID-19 patients is administered intravenously.

Trials are in process testing the IV version in outpatient settings like infusion centers and nursing homes.

The company is also exploring the potential of remdesivir combo therapies such as JAK inhibitor baricitinib [Eli Lilly’s (LLY -0.2%) Olumiant] and IL-6 inhibitor tocilizumab [Roche’s (OTCQX:RHHBY -0.3%) Actemra]. The corticosteroid dexamethasone is another prospect considering the positive data released last week.

The next wave of studies will include vulnerable patient populations, including children, pregnant women and those with end-stage renal disease.

On the supply front, the company expects to produce more than 2M treatment courses by year-end and “many millions” more next year.

https://seekingalpha.com/news/3584981-gilead-to-launch-study-of-inhaled-formulation-of-remdesivir