Biotech’s important upcoming data

Late-stage data are expected for Apellis; Ionis and Biogen tackle ALS; and Mirati awaits combination results.

Evaluate Vantage has delved into upcoming data readouts due in the third quarter for companies with a market cap of $1bn plus, and here Apellis stands out. The group will be hoping its complement inhibitor pegcetacoplan can succeed where others have failed.

Meanwhile, Ionis and Biogen will release late-stage results in amyotrophic lateral sclerosis, an area littered with previous failures, and combination data are due from Mirati’s Kras inhibitor adagrasib in lung and colorectal cancers. 

Targeting complement

Apellis is expecting phase 3 data with its intravitreal formulation of pegcetacoplan in geographic atrophy, an advanced form of dry age-related macular degeneration. The group believes it can succeed where other complement-targeting agents, such as Roche’s lampalizumab and more recently Gemini's GEM103, have struggled to show a benefit.

Apellis's confidence comes from the project's mechanism of action: by inhibiting C3 pegcetacoplan knocks out all three pathways involved in the complement system. Other experimental agents have tended to inhibit only one pathway, so pegcetacoplan could have a stronger effect, Apellis reckons.

That theory will be put to the test with Derby and Oaks studies, whose primary endpoints are a reduction in the growth of the GA lesion at month 12 with pegcetacoplan versus sham injection. One potential stumbling block could be choroidal neovascularisations, or abnormal blood vessels, which were seen in intravitreal pegcetacoplan’s phase 2 trial, Filly. Another worry is patients missing doses due to Covid-19 disruption.

If intravitreal pegcetacoplan does succeed, it could have the GA market to itself for a while. Evaluate Pharma's consensus forecasts that the project will bring in $1.2bn in 2026.

Kras combinations

Amgen’s Kras G12C inhibitor Lumakras gained an early US approval in second-line lung cancer in May, and now Mirati is gearing up for data with its similarly acting adagrasib. The phase 1/2 Krystal-1 study is combining adagrasib plus Keytruda in NSCLC, and adagrasib plus Erbitux in colorectal cancer; updated monotherapy and initial combination results are expected next quarter.

So far, adagrasib monotherapy has bested Lumakras in terms of efficacy. At last year’s Triple meeting adagrasib showed an overall response rate of 45% in NSCLC, versus 37% in Lumakras's phase 2 Codebreak-100 study.

However, at present Amgen has the larger dataset and the edge when it comes to safety. 14% of adagrasib-treated patients suffered QT prolongation which carries a risk of sudden cardiac death, an issue that has not been seen with Lumakras.

Mirati plans to file for accelerated approval in second/third line NSCLC in the second half of the year. 

ALS hopeful

The next big readout in ALS will concern the phase 3 study of tofersen, which Biogen licensed from Ionis in 2018. The field desperately needs a win; recent failures include Brainstorm Cell Therapeutics' cell therapy NurOwn and Orphazyme's arimoclomol (Arimoclomol failure leaves Biogen/Ionis exposed, May 7, 2021)

Tofersen is an antisense medicine targeting superoxide dismutase 1 (SOD1). A mutation in the SOD1 gene is the genetic driver in approximately 2% of ALS cases – this is thought to cause misfolded proteins leading to degeneration of motor neurons.

The Valor study has three segments, and it is part C, testing a 100mg dose, that will yield data. The study includes 99 patients with a confirmed SOD1 mutation, and the primary efficacy endpoint is change from baseline in ALSFRS-R total score, a measure of disability, at week 28. 

Data from parts A and B, which tested ascending doses of tofersen, showed a knockdown of cerebrospinal SOD1 protein, which was highest with the 100mg dose. There were also benefits on the ALSFRS-R scale, with a 1.19-point decrease with the 100mg dose versus a 5.63-point fall with placebo. A lower score represents worsening function. 

A phase 3 in presymptomatic SOD1 ALS patients called Atlas is also under way.

The table below contains a fuller list of upcoming catalysts with consensus forecasts from Evaluate Pharma. A look at big pharma clinical catalysts can be found here.

Q3 clinical catalysts (excludes Covid-19 data)
Product Company  Therapy area Q3 clinical catalyst 2026e indication sales ($m) Note/Vantage coverage
Adagrasib Mirati NSCLC, colorectal cancer Ph1/2 Krystal-1 monotherapy data and combination data (+Keytruda in NSCLC, + Erbitux in CRC) 1,608 See text
Repotrectinib Turning Point/Zai Lab Solid tumours (harbouring ALK, ROS1, or NTRK1-3 rearrangements) Enrollment and data update from Ph2 Trident-1 in H2 1,364 Need to see evidence of durability (Turning Point on the straight track, but to where?)
APL-2 (intravitreal pegcetacoplan) Apellis Geographic atrophy secondary to AMD Ph3 Derby and Oaks 1,184 See text
AXS-05 Axsome Treatment resistant depression Ph2 Merit H2 893* Vs placebo, the first study Stride-1 against bupropion failed (Axsome trips up), Pdufa in August for major depressive disorder
Brukinsa (zanubrutinib) Beigene 1L CLL Ph3 Sequoia (zanubrutinib vs bendamustine + rituximab) 821 Timing guided to 2021, CLL market dominated by Imbruvica
Anavex 2-73
Anavex Rett syndrome Ph2/3 Excellence H2 paediatric 521 Potentially pivotal study, still waiting for results from Avatar study in adult Rett syndrome, guided to mid year
Theravance Symptomatic neurogenic orthostatic hypotension Ph3 Sequoia 348 The company’s first wholly-owned asset, encouraging Ph2
SER-287 Seres Mild-to-moderate ulcerative colitis Ph2b Eco Reset top line mid year, pharmacology data H2 309 Microbiome modulator
Etrasimod Arena Crohn's disease Ph2 Cultivate dose-ranging data H2 175 Potential readthrough to ongoing Ph3 ulcerative colitis studies due early 2022
Zanidatamab Zymeworks 1L Her2 expressing gastroesophageal adenocarcinoma Ph2 plus chemo, H2 146 Keytruda's approval was based on Keynote-811 interim: Keytruda + Herceptin + chemo demonstrated an ORR of 74% (vs. 52% placebo) and a mDOR of 10.6 months (vs. 9.5 months)
Ionis/Biogen ALS Ph3 Valor H2 138 See text
RGX-314 suprachoroidal Regenxbio Wet AMD Safety data ph2 AAViate (vs Lucentis) 90 Anti-VEGF gene therapy, Adverum's therapy had a toxicity scare (Adverum halt raises more gene therapy questions)
RP-L301, RP-L401 Rocket Pharmaceuticals PKD, infantile malignant osteopetrosis  Update with RP-L301 in PKD in 2H21, first look at data with RP-L401 in IMO 85,
Gene therapies, had been expecting more data with RP-A501 in Danon disease but trial put on clinical hold for additional risk mitigation
Ionis-MAPTRx (BIIB080) Ionis/Biogen Mild Alzheimer's disease Ph1/2 H2 - Antisense oligonucleotide (ASO) targeting tau 
SL-172154 Shattuck Labs Ovarian cancer Ph1 dose escalation due H2 - A dual CD47/SIRPα inhibitor and CD40 agonist, IPO last Oct raised $232m
Theravance Ulcerative colitis Ph2b/3 Rhea - Gut-selective oral pan-JAK inhibitor, the delay with crohn's disease data to Q4 has pushed out timeline for JNJ opt-in decision until Q1 
OP-1250 Olema Oncology HR+/HER- breast cancer Ph1 initial data - Completed $240m IPO last Nov, OP-1250 is a complete estrogen receptor antagonist, Sanofi has the most advanced project amcenestrant
INCB86550 Incyte Solid tumours Ph1 - Oral PD-L1
*Includes forecasts for major depressive disorder. Sources: Evaluate Pharma, company releases, analyst notes &

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