I thought it might be helpful to combine and update information from some previous posts. The result is twenty reasons I hold in expectation that pharma will move to license/acquire trofinetide prior to commencement of Phase 3 in Rett syndrome.
- There is a strong, unmet need served by trofinetide. Currently, there are no approved drugs for the treatment of either Rett Syndrome or Fragile-X.
- Neuren has already received orphan drug designation for both Rett Syndrome and Fragile-X in the US and in the EU. Orphan drug designation confers 7 years’ exclusivity in the US and 10 years’ exclusivity in the EU. Pharma loves exclusivity.
- Granted patents for trofinetide extend until 2032.
- There is a strongly supportive rare disease community for both Rett and Fragile-X. This has positive implications for patient recruitment, lobbying of the FDA and speed of market penetration.
- Fast rate of enrolment and high rate of compliance during last Rett trial bodes well for recruitment into Phase 3.
- There are attractive financial incentives for any pharma taking over development at this stage. A US pharma which licensed or acquired trofinetide could not only run a Phase 3 trial for very modest outlay due to shorter trial duration and lower patient numbers, it would also be eligible for a further 50% R &D rebate on those costs. The cherry on top is trofinetide’s potential eligibility for a Paediatric Priority Review Voucher. Such vouchers, which guarantee shorter time frames for drug approval, are able to be on sold to other pharma. Sale prices since 2015 of these lucrative vouchers have been between US$125 million and US$350 million.
- Trofinetide (and Neuren's second candidate drug, NNZ-2591) can potentially treat a wide range of neurological conditions which share common cause and effect. In addition to Rett Syndrome, and Fragile-X, these include TBI and concussion, idiopathic autism, Parkinson’s disease, Alzheimer’s, MS, schizophrenia, stroke, cognitive impairment, depression and anxiety.
- Trofinetide has demonstrated a strong safety profile over multiple trials. More than 300 patients have now been dosed without the occurrence of any trofinetide-related, serious adverse events.
- Trofinetide has already demonstrated a range of clinical benefits in three separate, double-blind, randomized, placebo-controlled Phase 2 trials – two Rett trials (53 and 82 patients) and one Fragile-X trial (70 patients).
- Rett syndrome clinical experts are supportive of trofinetide. Following detailed analysis of the data from the most recent trofinetide trial, it was stated that “Rett syndrome clinical experts were unanimous in their view that safety and tolerability of trofinetide is not presenting as a limitation or concern and that the efficacy results are strongly supportive of trofinetide having a clinically meaningful effect on many of the core signs and symptoms of Rett syndrome.” (2016 Annual Report)
- In the latest trial, the extent of efficacy measured by each of the RSBQ, CGI-I and RTT-DSC scales correlated with the level of exposure to trofinetide. The extent of the correlation was also found to increase as the duration of treatment increased. The company has stated that this positive pharmacokinetic-pharmacodynamic relationship provides independent evidence of a direct biological effect.
- Neuren previously stated that it intended to use a Phase 3 dosing regimen designed to achieve consistent drug exposure in subjects regardless of their weight. The FDA has agreed to this request.
- Neuren previously stated that it was confident that the Rett Syndrome Behaviour Questionnaire (RSBQ) and the Clinician Global Impression of Improvement (CGI-I) could provide appropriate and well validated measures for a pivotal Phase 3 study (2016 Annual Report). The FDA has agreed.
- There is a current favourable environment for development of orphan drugs. At both a political and regulatory level, there is strong support for facilitating the approval of treatments for rare diseases. President Trump has voiced his personal support and the newly-appointed FDA Commissioner has voiced broad support for regulatory accommodation re “statistical certainty in rare disease therapies” and specific support of Bayesian approaches to statistical design.
- There is strong competitive interest by pharma in therapies for Rett Syndrome, orphan diseases and neurodevelopmental disorders. Pharma with expressed interest in these three areas include Novartis, Roche/Genentech, Shire, GSK, Teva, Sanofi/Genzyme, Takeda and Eli Lilly.
- Neuren has considered its options and is motivated. It has sought advice from Leerink Partners. It has stated that, following the announcement of the Rett syndrome study results in March this year, the company has continued to receive a wide level of interest in the trofinetide programs from pharmaceutical companies around the world. It has also stated that it would give due consideration to these offers after the meeting with the FDA (which was announced this week).
Examples of Orphan Drug Deals executed this year
Example 1
In a deal with headline value of US$380 million (~ AU$500 m), Roche agreed to pay US$175 million upfront plus US$205 million in milestone payments and potential tiered double-digit royalties for BMS-986089, a potential treatment for Duchenne muscular dystrophy (DMD). The drug is currently being studied in a Phase 1/2 trial which is estimated to complete in late 2020. There is just one already approved drug in DMD, and that is indicated for one subset of the DMD population, but there are another 40 drugs in development which are targeting this condition.
Example 2
Biogen agreed to pay US$300 million upfront and as much as a further US$410 million in milestone payments for BMS-986168, a Phase-2 ready drug in development for progressive supranuclear palsy (PSP). There are no current treatments for PSP. BMS-98618 has also been identified as a potential treatment for Alzheimer’s disease and Biogen intends to also study the drug in this indication. Because the drug was previously acquired by BMS as part of its acquisition of iPerian in 2014, Biogen was required to assume all remaining BMS obligations to iPerian as part of this deal. Payments to iPerian could total up to US$550 million in remaining milestones, including a near term US$60 million milestone, plus royalties. Hence, if BMS-986168 were to be successful and all milestones were hit, Biogen stands to fork out US$1.26 billion, plus royalties.