HIGH IMPACT – Roche announced positive results from its COMMODORE1 and 2 studies of crovalimab in PNH patients.

  • COMMODORE2 (naïve study) met co-primary endpoint of transfusion avoidance and control of hemolysis (LDH). Crovalimab was non-inferior to eculizumab.
  • COMMODORE1 (switch study) efficacy and safety data supported a favorable benefit-risk profile of crovalimab.
  • Based on these results Roche will file for crovalimab globally. Chugai in a separate press release also confirmed plans for filing in Japan.
  • No further details of the data were provided. Details will be presented at an upcoming meeting, likely EHA in June 2023

inThought Analysis

  • With these positive results,  crovalimab will likely get approval in US around mid-2024
  • Recall that COMMODORE1 primary outcome was changed from control of LDH to safety last year, but secondary outcomes still measure efficacy in patients switching from eculizumab. Both studies had a non-randomized arm with patients <18 yrs and COMMODORE1 also included patients who were on off-label doses of eculizumab (higher than 900mg and/or more frequently than Q2W), those on ravulizumab and those with known mutations in C5 gene. Roche is therefore likely to receive a broad label for crovalimab in PNH.
  • We will need to see the detailed data from COMMODORE1 to determine whether patients switching from eculizumab to crovalimab are able to maintain disease control. Although likely not powered to show non-inferiority, it will also be important to see whether the efficacy is similar to Ultomiris.
  • Given similar efficacy, the availability of crovalimab will split the C5i market between once monthly SC (crovalimab), once weekly SC (Ultomiris SC), once every 2w IV (Soliris), or once every 8w IV (Ultomiris).
  • Since most patients in the US and EU5 have already been switched from Soliris to Ultomiris, physicians will be keen to see the results in patients who were switched from Ultomiris to crovalimab. Recall that while Ultomiris had shown non-inferiority to Soliris in its registrational trials, numerically it performed better than Soliris with better control of intravascular hemolysis. With iptacopan entering the market, patients who are considering switching from Soliris/Ultomiris are likely to opt for an oral therapy. Additionally, crovalimab will likely be under pricing pressure soon after its launch with biosimilars expected to hit the US market in 1Q 2025 and even earlier in EU.
  • Crovalimab’s main opportunity lies in geographies where Soliris and Ultomiris have not been approved yet. Hence Roche’s strategy to file in China first with approval expected in mid-2023. However, even there it was narrowly beaten with Soliris winning approval earlier this year. An at home once monthly SC administration will still remain a significant advantage to Soliris.

Source: Roche Press Release, Chugai Press Release

MODERATE IMPACT – The National Institute for Health and Care Excellence (NICE) has issued a Final Evaluation Document recommending Translarna (ataluren) for reimbursement and use across the National Health Service (NHS) in England and Wales.

  • Translarna is licensed in multiple countries, including Great Britain, Northern Ireland, and the European Economic Area, for treating nonsense mutation DMD in ambulatory patients aged 2 years and older.
    • Ataluren remains an investigational new drug in the United States.
  • The final evaluation document stated that the cost-effectiveness estimates were uncertain because of the limitations in the clinical effectiveness data. But, with the commercial arrangement agreed after the second committee meeting, the cost-effectiveness estimates for ataluren are below the range that NICE usually considers acceptable for highly specialized technologies. Therefore, ataluren is recommended.

inThought Analysis

In October 2022, NICE’s draft guidance was published not recommending Translarna to be covered for DMD, stating that benefits did not justify the cost. The final evaluation document states that Translarna was only recommended because of a commercial arrangement that makes Translarna available at a discount. The details of the discount are confidential.

At JPM 2023, PTC announced it achieved $289M in revenue for Translarna, with growth driven by new patients in existing geographies and continued geographic expansion. The NICE evaluation and agreement with NHS will help solidify newly diagnosed and existing patient access to Translarna in England and Wales, but how the magnitude of the discount will affect revenue is unclear. PTC continues to seek approval in the U.S., but the FDA’s concerns over efficacy remain.


Source: PTC Press Release, NICE Final Evaluation Report

HIGH IMPACT – BioMarin released 3-year data from its ongoing global phase 3 GENEr8-1 study for Roctavian in adults with severe hemophilia A.

  • Mean/median FVIII activity (chromogenic) at year 3 was 18.8/8.4% (n=132). The 3 year mean FVIII activity was slightly better than 3 year mean activity of 15.2% listed in the Roctavian SmPC (n=19). Mean/median ABR for all bleeds in year 3 was 1.6/0.0 (see below for treated bleeds). At the end of year 3, 92% of patients remained off prophylaxis, a reduction from the 95% at year 2
  • BioMarin reported 4 year data (n=17) for the first time from this trial. Mean/median FVIII was 15.2/7.4%. Mean/median ABR for all bleeds in year 4 were 1.6/1.0 (see below for treated bleeds)
  • BioMarin has executed an outcomes-based agreement with one of the three largest health insurance groups in Germany and is targeting signing additional agreements in Germany in the coming weeks. BioMarin stated there are 40 patients queued for pre-treatment screening in Germany


Phase 3 (6e13 vg/kg dose)
In Year 3*In Year 4**
FVIII Activity (chromogenic)Mean18.815.2
ABR for treated bleedsMean1.00.8
ABR for all bleeds (regardless of being treated with exogenous FVIII replacement)Mean1.41.6
Annualized FVIII Utilization (infusions per year)Mean8.411.1

*N=132 (FVIII Activity); N=112 (ABR and AFR). Two of these patients discontinued from the study prior to reaching Year 3. FVIII imputed to be 0 IU/dL; no imputation was carried out for ABR and AFR.
**N=17. One of these patients discontinued from the study prior to reaching Year 4. FVIII activity imputed to be 0 IU/dL; no imputation was carried out for ABR and AFR.

  • At the end of year 3, 92% of patients remained off prophylaxis. Those who returned to FVIII or emicizumab prophylaxis did so safely
  • Two patients discontinued from the study during year 3 and one additional patient discontinued from the study during year 4. The press release did not provide additional information on these discontinuations


  • Safety profile was consistent with that which was previously reported
  • No delayed-onset treatment related AEs or treatment-related SAEs or Grade 3 events attributed to Roctavian or corticosteroid use
  • No participants have developed inhibitors to FVIII, thromboembolic events or malignancy associated with Roctavian

Regulatory Status:

  • The company continued to state that the March 31 PDUFA date may be extended
  • FDA has completed pre-license inspection of manufacturing facility in early December – BioMarin stated that all comments are addressable

EU Launch Update:

  • The three largest health insurance groups BioMarin is targeting represent 80% of German citizens
  • The OBAs in Germany are multiyear agreements which provide companion diagnostic testing and reimbursement of Roctavian and cover payer risk of patients potentially returning to prophylaxis through direct BioMarin financial commitment in return for substantial and full upfront payment
  • BioMarin has had meetings with authorities in France and has submitted a reimbursement dossier in Italy

Additional details to year-3 data will be presented at a future scientific conference (In 2022, BioMarin presented 2 year results at EAHAD, but a presentation is currently not on the EAHAD 2023 schedule).

inThought Analysis

While the FVIII activity is still declining over time, the rate of decline continues to decrease:  51% decline from year 1 to 2; 39% decline from year 2 to 3; 12% decline from year 3 to 4 (only 17 patients).  This is in general similar to the phase 1/2 declines, which have continued out to 6 years now but have also shown a reduction in the rate of decline.

While median ABR for treated bleeds remained 0.0 at year 3 and the limited number of patients in year 4, the median ABR for all bleeds increased to 1.0 at year 4 – this increase may spark questions about efficacy, especially if it eventually translates into treated bleeds.

Additionally, the increase in the number of patients returning to prophylaxis may lead to some patients waiting to see how fast this percentage increases over time.

FDA had previously requested 3-year data for Roctavian to evaluate longer-term efficacy and safety. BioMarin has continuously advertised to investors that the FDA review may take 3 months longer than the March 31st PDUFA date, which would imply an approval in June 2023 instead. The 3-year mean FVIII activity for all the patients of 18.8 (CSA) is only slightly greater than the EU SmPC with 19 patients at 15.2 (CSA), providing BioMarin only marginal benefit with the full dataset going into the FDA review process.


Source: BioMarin Press Release

MODERATE IMPACT – Biogen and Alcyone entered into a license and collaboration agreement to develop Alcyone’s ThecaFlex DRx System, an implantable medical device intended for subcutaneous delivery of antisense oligonucleotide (ASO) therapies into the intrathecal space in patients with spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS).

  • The ThecaFlex DRx System would allow routine subcutaneous (SC) administration of ASO therapies to the cerebrospinal fluid. The ThecaFlex DRx System has received a CE Mark in Europe and Breakthrough Device Designation from the FDA.
  • Biogen and Alcyone will jointly collaborate on the clinical development of the system for ASO therapies, and Alcyone will be solely responsible for its manufacture and commercialization.
  • The ThecaFlex DRx System will initially be evaluated with Spinraza in SMA.

inThought Analysis

Biogen signed a research collaboration agreement with Alcyone to ” improve intrathecal delivery therapies” in 2017. Even during preclinical studies of Spinraza, Ionis and Biogen discussed the need for developing a SC device that would bypass the need for the intrathecal administration of the drug, as SMA patients have challenging anatomy posing increased challenges to lumbar punctures. In previous studies of systems that combined an intrathecal catheter and an implantable infusion port, devices allowed Spinraza to be administered safely and effectively in an outpatient setting. Still, patients experienced complications related to the administration device. All treatment-related adverse events in one study were attributable to the device and not Spinraza. Although the partnership seems promising, any indwelling device accessed repeatedly is subject to mechanical failures and infections.

With competitors in the SMA space providing greater patient flexibility through oral administration (Evrysdi) and a potentially one-time gene therapy treatment (zolgensma), Biogen is likely to continue exploring options to improve patient experience and for ease of access to Spinraza.


Source: Biogen Press Release

HIGH IMPACT – Madrigal announced positive topline results from the pivotal Phase 3 MAESTRO-NASH trial of resmetirom (THR-β agonist) in non-cirrhotic NASH with liver fibrosis. MAESTRO-NASH achieved both liver histological endpoints and potentially clinically meaningful effects with 80 mg and 100 mg doses of the drug, relative to placebo.

Study summary:

  • 52-week phase 3 study in F1B-F3 patients
  • >1,000 patients enrolled in US and Europe for wk 52 analysis
  • Patients randomized 1:1:1 to receive resmetirom 80 mg, resmetirom 100 mg, or placebo taken orally once daily

Efficacy results:

  • Dual primary endpoints of NASH resolution and no worsening of fibrosis and ≥ 1-stage improvement in fibrosis with no worsening of NAS were met
  • Key secondary endpoint of LDL-C lowering was also met
  • Biopsies were read by two central pathologists; each pathologist’s score showed statistically significant magnitude of response at both doses for both histology endpoints
  • Endpoints were achieved independent of baseline fibrosis stage and diabetes status
  • Additional secondary histology endpoints were achieved at both doses; ≥2 point reduction in NAS with no worsening of fibrosis, ≥2 point reduction in NAS with ≥1-stage improvement in fibrosis, NASH resolution (with ≥2 point reduction in NAS) with ≥1-stage improvement in fibrosis and 2-stage reduction in fibrosis without worsening of NAS
  • Statistically significant reduction from baseline in liver enzymes, reductions in atherogenic lipids and lipoproteins, fibrosis biomarkers and imaging tests (MRI-PDFF, CAP and liver stiffness measures) was reported

Safety results:

  • Resmetirom was safe and well-tolerated at both the 80 mg and 100 mg doses
  • The frequency of SAEs was similar across treatment arms, and the rate of study discontinuation for AEs was low

Upcoming milestones:

  • Madrigal intends to file a NDA seeking accelerated approval of resmetirom for the treatment of non-cirrhotic NASH with liver fibrosis in 1H 2023
  • The company intends to submit primary results for publication in a peer-reviewed journal and present study results at a future scientific congress

inThought Analysis

  • The MAESTRO-NASH results have beaten all expectations in meeting not only both primary endpoints of NASH resolution and improvement in fibrosis but also key secondary endpoints including multiple non-invasive tests. Street reacted positively with Madrigal’s stock tripling following the announcement.
  • While Intercept is poised to file for Ocaliva by end of 2022, making it the first of the two to potentially enter the market, the drug has been marred with safety and tolerability concerns, particularly around hepatic safety. Moreover, the phase 3 study in compensated cirrhosis has failed to show any benefit of the drug. In contrast, resmetirom has been shown to be relatively well tolerated, besides the GI issues, and is expected to have a relatively smoother path to approval.
  • Both resmetirom and Ocaliva are oral drugs, and therefore have an advantage over other promising late-stage drugs such as semaglutide or efruxifermin, which have to be administered subcutaneously.
  • While competitors such as Inventiva’s lanifibranor and Akero’s efruxifermin have achieved both endpoints of NASH resolution with no worsening of fibrosis AND improvement in fibrosis with no worsening of NASH in their phase 2 programs, they are yet to replicate those results in their larger phase 3 programs.
  • NASH represents an enormous unmet need, and has historically been a drug development graveyard; a first entrant to the market will enjoy a significant advantage.
  • While Intercept already has had significant commercial experience with Ocaliva, which is marketed for primary biliary cirrhosis, Madrigal will have to build up its commercial presence from scratch in order to market resmetirom. These favorable results brings Madrigal to the forefront as a lucrative acquisition target by large pharmas, perhaps Pfizer, Novartis or Amgen.


Source: Madrigal Press Release, Madrigal Presentation