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In October 2022, NICE’s draft guidance was published not recommending Translarna to be covered for DMD, stating that benefits did not justify the cost.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

HIGH IMPACT – CSL/uniQure’s Hemgenix (etranacogene dezaparvovec, Etranadez) was approved by the FDA for hemophilia B.

Key Takeaways

  • Hemgenix was approved for adults with hemophilia B who currently use FIX prophylaxis, have current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes
  • Hemgenix is the first hemophilia B gene therapy approved and the first hemophilia gene therapy approved in the U.S. (Roctavian was approved in August for hemophilia A in Europe)
  • CSL emphasized that Hemgenix is the first therapy for hemophilia B that offers patients and caregivers the possibility of freedom from regular, ongoing infusions
  • The initial reports suggest an initial list price of $3.5 million


  • Steven Pipe quote from CSL press release emphasized the freedom from regular infusions: “HEMGENIX is unique in its approach to increasing mean factor IX activity and hemostatic protection in those with hemophilia B, and today’s approval could fundamentally transform the treatment paradigm for this life-long condition,” said Dr. Steven Pipe … a lead investigator in the HOPE-B study. “As a clinician, I look forward to being able to provide a new treatment option that may help patients treated with HEMGENIX become free from the regular infusion schedule that many people living with hemophilia B rely on to protect them from the debilitating effects of the condition.”

Details of USPI

Indication:  Adults with hemophilia B who: currently use FIX prophylaxis therapy, have current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes


  • 2e13 genome copies (gc) per kg. Administered as an IV infusion at a rate of 500 ml/hr (8 mL/min). Provided in kits containing 10 to 48 single use vials. For an average 72kg patients, 144 mL and 15vials will be required
  • The USPI specifically states that Hemgenix can only be administered once

Patient Selection:

  • Perform FIX inhibitor testing – if test and retest are positive, do not administer Hemgenix
  • Perform liver health assessments including: ALT, AST, ALP, total bilirubin and hepatic ultrasound and elastography. In the case of liver abnormalities, consider consultation with a hepatologist to assess eligibility for Hemgenix.
  • The USPI states that the safety and efficacy of Hemgenix has not been studies in patients with advanced hepatic impairment and Hemgenix was not studied in patients with severe renal impairment
  • A test for AAV5 neutralizing antibodies is not required.  The USPI discusses the results in patients who were positive for preexisting AAV5 NAb using an unvalidated assay in the Hemgenix trials.  Patients intending to receive Hemgenix are encouraged to enroll in a CSL study to measure pre-existing NAb to AAV5 to determine any affect on the risk of bleeding
  • The prescribing information states that 6 geriatric subjects (age 68-75) were in the trials with no meaningful differences in safety and efficacy profiles

Monitoring and warnings

  • Monitor for infusion reactions during and for at least 3 hours after end of infusion.  If symptoms occur, slow or interrupt administration. Re-start at a slower rate once resolved
  • Closely monitor ALT and AST levels once per week for 3 months. Continue to monitor in all patients who developed elevated liver enzymes until they return to baseline.
  • Consider corticosteroids if liver enzyme elevation (above normal limits or 2x patient’s base level) occurs. Starting dose of 60mg with tape (week 2 – 50mg; week 3 – 30mg; week 4 – 30mg; maintenance until ALT returns to baseline – 20mg and then reduce by 5mg/week). Mean duration of steroid use in trials was 81.4 days (51-130 days)
  • Hepatocellular carcinogenicity: For patients with preexisiting risk factors (e.g. cirrhosis, advanced hepatic fibrosis, hepatitis B or C, NAFLD, chronic alcohol consumption, NASH, and advanced age) perform regular (annual) liver ultrasound and alpha-fetoprotein testing. The prescribing information states that integration of AAV vector DNA into the genome may carry the theoretical risk of hepatocellular carcinoma development. It also states that no Hemgenix associated clonal expansion or carcinogenicity has been observed in clinical studies
  • Monitor FIX activity – suggestion of weekly for 3 months.
  • Monitor for FIX inhibitors if bleeding is not controlled or FIX levels decrease


  • Shipped and stored at 2 to 8 degrees C

Adverse Reactions: elevated ALT, headache, blood creatine kinase elevations, flu-like symptoms, infusion-related reactions, fatigue, malaise and elevated AST

Clinical data

  • The USPI contains a chart with stable FIX levels out to month 24 with the median FIX activity at month 24 of 33.9 (4.7, 99.2) using a one-stage assay
  • Mean ABR from months 7 to 18 was 1.9 compared to 4.1 during the lead in period. Subjects with zero bleeds was 63% versus 26% in the lead-in study
  • 2 patients did not stop prophylaxis.  One additional patient received prophylaxis for 20 weeks between days 396 and 534.

inThought Analysis

The first gene therapy approved for hemophilia was BioMarin’s Roctavian in the EU. The FDA is also set to decide on Roctavian in 2023 and has reported plans to consult an advisory committee on the company’s approval application. While there are differences in the drugs, Hemgenix label appears to be less restrictive and more favorable in terms of appropriate patients and post-dose monitoring requirements compared to Roctavian’s SmPC.  FIX and liver enzyme monitoring are only being required for 3 months versus up to 2 years for Roctavian.  Unlike the Roctavian SmPC, the Hemgenix USPI does not mention restrictions such as active infections, refraining from drinking alcohol, and does not require testing for AAV5 NAbs. Also, this approval did not require an FDA adcomm.

Overall, regulatory agencies are showing they will not make class-wide restrictions on gene therapies, and are practicing flexibility in approving and labeling of two AAV gene therapies for the same disease.


Source: FDA Press Release, BiopharmaDive