Go or no go? Bristol’s Lag3 debut
March Pdufa dates are set for relatlimab as well as Akebia’s vadadustat, while Amylyx’s ALS drug heads for a panel.
Next month Bristol Myers Squibb’s relatlimab will likely become the first approved MAb targeting Lag3, but competition is not far behind, and other immuno-oncology approaches are hotting up.
Meanwhile the outcome for Akebia’s vadadustat does not look so rosy, owing to the safety concerns plaguing the HIF-PH inhibitor class that led to Fibrogen’s knockback last year. Lastly, Amylyx’s AMX0035 will go before an advisory panel for use in ALS, but the outcome will be complicated by limited clinical data and strong patient advocacy.
Not lagging behind
A green light is expected for Bristol’s anti-Lag3 relatlimab next month given its impressive PFS data. The antibody is administered as a fixed-dose combination with Opdivo, and the phase 2/3 study Relativity-047 in unresectable or metastatic melanoma showed a median PFS of 10.1 versus 4.6 months for Opdivo alone.
Adverse event analyses were also positive, pegging relatlimab as a less toxic replacement for Bristol’s own Yervoy. Just 18.9% of patients given the relatlimab combo in Relativity-047 had severe treatment-related adverse events, versus 59.0% in the Opdivo plus Yervoy cohort in Checkmate-067 (Asco 2021 – Bristol’s Lag3 case for a replacement for Yervoy, May 19, 2021).
Bristol might be first past the post with relatlimab, but competition both within the Lag3 class and in other immuno-oncology approaches, such as Tigit, is intensifying.
Merck’s anti-Lag3 MAb favezelimab, co-formulated with Keytruda, is next in line after starting a phase 3 study in colorectal cancer at the end of last year, while several other competitors are also in play. In terms of Tigit Roche expects to report pivotal data on tiragolumab this year.
History on repeat
The troubled HIF-PH inhibitor class has another pass at US regulators next month. This time it is Akebia’s turn with vadadustat, an oral anaemia project filed for use in chronic kidney disease patients either on or not on dialysis.
Vadadustat's biggest problem is a cardiac toxicity signal evident in non-dialysis patients. This makes it likely that the project will follow in the footsteps of Fibrogen’s roxadustat, which last year was handed a complete response letter due to cardiac and other toxicity issues.
Glaxosmithkline is another player in the space, and will be keeping a close eye on the Akebia decision. Glaxo plans to file its offering, daprodustat, in the first half of this year.
Big day for Amylyx
A panel will meet towards the end of March to discuss Amylyx’s ALS treatment AMX0035, which was filed on the back of a single phase 2 study, Centaur.
Centaur showed a statistically significant improvement with AMX0035 versus placebo on ALSFRS-R, a functional rating scale, over 24 weeks, and on overall survival. However, the trial was small, in just 137 patients, and more patients in the treatment cohort dropped out because of adverse events, the most common being diarrhoea.
A confirmatory phase 3 study called Phoenix tests a 48-week treatment course, but data are not due until 2024.
ALS is a condition with significant unmet need, and many therapies have failed in the clinic. With pressure from patient advocacy groups the FDA could back AMX0035 despite its limited clinical data. Originally the agency wanted to see data from another placebo controlled trial before Amylyx filed, but after discussions the regulator apparently changed its stance (Amylyx changes its mind about an early filing, September 15, 2021).
The panel outcome is key for Amylyx, which only went public in January. The company boasts a market cap of $1.6bn, but AMX0035 is its only clinical project.
The tables below lists first-time and supplementary US approval decisions, as well as advisory committee meetings, due next month, with consensus forecasts from Evaluate Pharma.
|Notable first-time US approval decisions due in March|
|Project||Company||Pdufa date||Indication(s)||2026e sales by indication (SBI) ($m)||Note/Vantage story|
|Relatlimab (Opdivo combo)||Bristol Myers Squibb||Mar 19||1L melanoma||437||See text|
|Marinus||Mar 20||Seizures associated with CDKL5 deficiency disorder (rare form of genetic epilepsy)||384*||Filed on positive Ph3 Marigold data, IV version has suffered delays due to supply issues|
|Mar 22||1L non-squamous NSCLC||-||Adcom voted 14-1 against approval (How China applicants could avoid the sintilimab scenario)|
(Ukoniq + ublituximab)
|TG Therapeutics||Mar 25||Chronic lymphocytic leukaemia & small lymphocytic lymphoma||691||Pdufa unlikely to be met as adcom is expected owing to a lack of OS benefit in Unity-CLL (TG slips out a nasty surprise for investors)|
|Mar 29||Anaemia due to CKD in adult patients on/not on dialysis||532||See text|
|Ryzneuta||Evive Biotech||Mar 30||Chemotherapy-induced neutropenia||-||-|
|Hugel America||Mar 31||Moderate-to-severe glabellar lines||249||-|
|Akeso/Sino||Est H1||3L nasopharyngeal carcinoma||-||How China applicants could avoid the sintilimab scenario|
|177Lu-PSMA-617||Novartis||H1||Radioligand therapy for mCRPC||851||Asco 2021 justifies Novartis’s radioligand Vision|
|Epsolay||Sol-Gel||Pending||Papulopustular rosacea||-||Pre-approval inspection had been scheduled for mid Feb|
|*For general epilepsy. Source: Evaluate Pharma (23 Feb) & company releases.|
|Advisory committee meeting in March|
|Project||Company||Adcom date||Indication||Peak sales (non-risk adjusted, $m)||Note|
|AMX0035 (sodium phenylbutyrate + taurursodiol)||Amylyx||Mar 30||ALS||1,820||See text, Pdufa Jun 29|
|Source: broker reports & FDA adcom calendar.|
|Supplementary and other notable approval decisions in March|
|Product||Company||Indication (clinical trial)||Date|
|Corium||Dementia due to mild, moderate or severe Alzheimer's disease||Mar 11 (resubmitted)|
|Fintepla||Zogenix/UCB||Seizures associated with Lennox-Gastaut Syndrome||Mar 25|
|Mezzion||Single ventricle heart disease||Est Mar 26|
|Reblozyl||Bristol/Merck||Anaemia in adults with non-transfusion-dependent beta-thalassemia (Ph2 Beyond)||Mar 27|
|Keytruda||Merck||2nd-line MSI-H/dMMR endometrial cancer (Keynote-158, cohorts D & K)||Mar 28|
|Oral testosterone replacement therapy||Mar 28 (tentatively approved in Dec, eligible for full approval on expiry of exclusivity period granted to Clarus Therapeutics for Jatenzo)|
|Lynparza||Astrazeneca||Adjuvant BRCA-mutated Her2-negative breast cancer (OlympiA)||Q1|
|Ozempic (2.0mg)||Novo Nordisk||Type 2 diabetes (Sustain Forte)||H1 (resubmitted, previous RTF)|
|Olumiant||Lilly||Atopic dermatitis (Breeze-AD programme)||Pending|
|Rinvoq||Abbvie||Ankylosing spondylitis and ulcerative colitis||Pending|
|Source: Evaluate Pharma & company releases.|