Portfolio Update Q4 2021
The fourth quarter 2021 provided multiple major milestones for our portfolio holdings such as clinical results, regulatory decisions and licensing deals. With the Omicron variant being highly transmissible but less harmful than previous SARS-CoV-2 variants, and the mRNA vaccine boosters providing good protection against Omicron, the focus for investors regarding pipeline updates has shifted back towards chronic and severe diseases. The clinical results for the biotechnology industry and our portfolio saw a mixed picture in the last quarter. The negative environment exaggerated market news, with positive updates not necessarily leading to higher valuations.
Many milestones including clinical trial data
Late stage trial read-outs were mixed in the last quarter of 2021. Sage Therapeutics reported further positive data for Zuranolone in the ongoing shoreline study in patients with major depression disorder (MDD). At 50 mg treatment and measured at day 15 following the initial two week treatment, 75% of patients achieved a response (at least 50% reduction from baseline) and 40% achieved a remission. Importantly, the large majority of patients treated for 14 days at 50 mg per day required either no or maximum one additional 14 day course of therapy to maintain an improved status. Sage and its development partner Biogen are planning to file Zuranolone for MDD in the US in late 2022, allowing for a potential market launch in late 2023.
Biogen reported results from its pivotal Phase III VALOR study of tofersen (BIIB067), an investigational antisense drug being evaluated for people with superoxide dismutase 1 (SOD1) amyotrophic lateral sclerosis (ALS). Tofersen did not meet the primary endpoint of change from baseline to week 28 in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R). Due to trends favoring tofersen across multiple secondary and exploratory measures of biologic activity and clinical function, Biogen announced to invest in the clinical study called ATLAS testing tofersen in pre-symptomatic individuals with a SOD1 genetic mutation and to broaden early access to ALS patients in expanded access program.
Radius Health reported on three Phase III studies in the fourth quarter of 2021. The ATOM study met its primary endpoint – the percentage change in lumbar spine (LS) bone mineral density (BMD) compared to placebo – demonstrating statistical significance after 12 months in male osteoporosis patients. The more important wearable study did not meet its primary endpoint of non-inferiority for the transdermal delivered abaloparatide 300 micrograms versus the subcutaneous delivered and approved Tymlos 80 micrograms in the percent change from baseline in lumbar spine (LS) bone mineral density (BMD) at 12 months. The patch demonstrated a 7.1% increase in lumbar spine bone mineral density versus subcutaneous Tymlos achieving 10.9%. Thus the patch, albeit its anabolic activity, missed the non-inferiority margin of 2.0%.
Radius partner Menarini for the company’s oncology asset elacestrant reported positive results for the EMERALD study. Both primary endpoints, showing statistically significant PFS in the overall population and ESR1 mutation subgroup were met. The safety profile of elacestrant exhibited in EMERALD was similar to that of the previous clinical trial. Given these results, Menarini and Radius plan on proceeding with regulatory submissions in both the US and in EU in 2022.
Promising proof-of concept data was reported by Relay Therapeutics and by Fate Therapeutics. Relay Therapeutics announced interim clinical data for RLY-4008, a highly selective irreversible and oral small molecule inhibitor of FGFR2, in a first-in-human trial in patients with FGFR2-altered cholangiocarcinoma and multiple other solid tumors. The data suggests that RLY-4008 is the first investigational therapy designed to selectively bind to FGFR2, and importantly, avoiding off‐isoform toxicities for the treatment of patients with FGFR2-altered tumors. In pan-FGFRi treatment-naïve cholangiocarcinoma patients, RLY-4008 demonstrated tumor shrinkage in all six patients, with three achieving confirmed partial responses. Three of these six patients remain on study and a fourth patient went on to surgery with curative intent. Further data from dose expansion cohorts can be expected during 2022.
Fate Therapeutics, another of our oncology portfolio companies, presented promising interim dose-escalation clinical data from its FT596 program in relapsed refractory B-cell lymphoma. The data presented demonstrates that off-the-shelf, iPSC-derived CAR NK cells can bring substantial therapeutic benefit to heavily pre-treated patients in urgent need of therapy. Over half of the patients treated with a higher single dose of FT596 in combination with rituximab achieved a complete response with a favorable safety profile that is clearly differentiated from CAR T-cell therapy. The company is expected to provide data for patients treated at yet a higher dose and for patients earlier in care, most importantly data on duration of response in 2022.
Moderna disclosed important updates for its mRNA vaccine candidates. Most importantly, the company presented reassuring data for its SARS-CoV-2 authorized booster, with the 50 microgram dose of mRNA-1273 increased Omicron specific neutralizing antibody levels by approximately 37 fold, versus the 100 microgram dose increasing the neutralizing antibody levels by 83 fold. Thus, the company plans to use mRNA-1273 as first line of defense against Omicron but at the same time develop an Omicron-specific variant vaccine (mRNA-1273.529), which has entered the clinic in January 2022. Next to the pandemic vaccine efforts, Moderna updated investors on its quadrivalent influenza vaccine (mRNA-1010) effectively boosted titers against all four strains in older and younger adults, with no significant safety concerns observed. The quadrivalent mRNA-1010 encodes for the hemagglutinin (HA) protein from four seasonal influenza viruses based on the recommendations of the World Health Organization (WHO), including seasonal influenza A/H1N1, A/H3N2 and influenza B/Yamagata- and B/Victoria-lineages. Importantly, Moderna is expected to present data in 2022 for mRNA-1011 that includes one additional hemagglutinin (HA) antigen and mRNA-1012 with two additional HA antigens. Separately, the company is also developing two next-generation flu candidates that incorporate neuraminidase antigens to broaden immunity beyond hemagglutinin (mRNA-1020, mRNA-1030), all being part of the company’s strategy to ultimately develop a pan-respiratory annual booster vaccine.
One of our pre-clinical companies, Generation Bio, is developing gene therapies devoid of viral packaging and viral vector biology. The company unfortunately updated investors in the fourth quarter that the latest generation of LNPs in combination with ceDNA plasmids did not maintain and translate expression levels from mice to nonhuman primate models. Thus, the company is back to the drawing board to develop functional LNP/ceDNA combinations that will translate into higher expression levels in NHPs and only then will move into human clinical trials. Strategically, this could lead to the ophthalmology programs jumping ahead of the liver targeting application, with further updates regarding the pre-clinical progress expected for 2022.
Numerous milestones with regard of regulatory decisions
BB Biotech’s portfolio holdings updated on multiple regulatory decisions in the fourth quarter 2021 such as
- Vyvgart (efgartigimod alfa-fcab) from Argenx was approved by the FDA for the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) antibody positive.
- Caplyta (lumateperone) from Intra-Cellular was approved by FDA to treat depressive episodes associated with bipolar I or II disorder (bipolar depression) in adults as monotherapy and as adjunctive therapy with lithium or valproate.
- Leqvio (inclisiran) from Novartis/Alnylam was approved by FDA an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (ASCVD), who require additional lowering of lowdensity lipoprotein cholesterol (LDL-C).
Beneficial collaboration in the last quarter of 2021
With M&A activity close to a standstill and no deals within the industry and our portfolio holdings, business development activities were of interest. AstraZeneca has entered into a new global development and commercialization agreement with Ionis Pharmaceuticals for eplontersen, formerly known as IONIS-TTR-LRX. Eplontersen is a ligand-conjugated antisense (LICA) investigational medicine currently in Phase III clinical trials for amyloid transthyretin cardiomyopathy (ATTR-CM) and amyloid transthyretin polyneuropathy (ATTR-PN). It is designed to reduce the production of transthyretin (TTR protein) to treat both hereditary and non-hereditary forms of TTR amyloidosis (ATTR). The companies will jointly develop and commercialize eplontersen in the US, while AstraZeneca will develop and commercialize it in the rest of the world, except in Latin America. Ionis will receive an upfront payment of USD 200 mn and additional conditional payments of up to USD 485 mn following regulatory approvals and up to USD 2.9 bn of sales-related milestones based on sales thresholds between USD 500 mn and USD 6 bn, plus royalties in the range of low double-digit to mid-twenties percentage depending on the region.