There have been—and always will be, as you can imagine in the fast-paced world of life sciences and pharma/biotech—any number of shifts and developments in various markets and pipelines and what the state of things is for any given disease indication and/or therapeutic pipeline. With that in mind, we offer here a roundup of various insights from London-based data and analytics company GlobalData over the past couple months on a range of areas from HIV and AD (Alzheimer’s disease) to rare diseases to dry eye and migraine.
HIV pipeline sees high levels of innovation targeting resistance and latency reversal
The human immunodeficiency virus (HIV) pipeline is robust, with 450 products in active development that display a high degree of novelty and diversity. Promisingly, there are 87 first-in-class products that act on a range of 50 molecular targets, which can broadly be classified as host or viral factors, indicating a high level of innovation in comparison with the marketed products.
The company’s recent report, “HIV: First-in-Class Therapies Target Major Unmet Needs Including Drug Resistance and Latency Reversal,” reveals that the majority of the 10 highest-ranking targets have demonstrated evidence, either in vitro or in vivo, of latency-reversing potential and/or efficacy in drug-resistant HIV strains. This encouraging trend demonstrates that first-in-class innovation is centered on addressing these major unmet needs in the HIV market.
“The persistence of latent HIV reservoirs in antiretroviral therapy (ART)-treated patients represents a major barrier to the development of a functional cure, while the global rise in HIV drug resistance compromises the significant advances in disease management that have been achieved since the 1980s,” said Sarah Elsayed, a pharma analyst at GlobalData. “However, the most pressing unmet need remains to be a cure that results in viral eradication.”
First-in-class targets were integrated into a proprietary matrix assessment that ranks them according to their therapeutic and commercial potential within HIV market. Interleukin 2 receptor subunit beta (IL2RB) was found to have the highest ranking. It has a role in stimulating the immune response by activating the potent IL-2 signaling pathway that results in suppression of viral replication eventually. Also, the drug candidate possesses latency-reversing potential as shown in the preclinical investigations. Other first-in-class targets with strong therapeutic potential include those targeting Toll-like receptor (TLR3) and Protein kinase C (PKC) family.
Furthermore, HIV vaccines have a strong presence in the overall pipeline (27.2 percent). Preventive and curative vaccines have received high attention in research recently, since they may potentially translate into a cure that will eradicate the virus and help control the HIV pandemic. Despite the promising outlook, vaccines have historically suffered from high failure rates due to the particular nature of HIV and the low clinical trial participation rates globally.
Cell/gene-based therapy is also being investigated in the early stages of development, with two first-in-class products, both of which are at the discovery stage. It is different from the conventional antiretroviral treatment, since it can potentially be translated into a revolutionary cure in the near future.
Elsayed concludes: “Although 60 percent of these pipeline drugs are still in early development, the innovation of molecular targets is promising and presents the potential to expand the existing HIV drug classes, which have not completely fulfilled the primary unmet need for long-acting therapies.”
Another blow for Alzheimer’s disease patients
Following the failure of a trial for two monoclonal antibody drugs for AD—Eli Lilly’s solanezumab and Roche’s gantenerumab—in patients that have a rare genetic mutation that causes early-onset AD, senior pharma analyst Alessio Brunello of at GlobalData said: “The data from the trial DIAN-TU that tested solanezumab by Eli Lilly and gantenerumab by Roche presented disappointing results in some earlier studies, but the doses in this study ranged up to four to five times higher and researchers had hoped that would prove more effective as was seen with Biogen’s aducanumab. However, in the DIAN-TU the very small sample size and the late increase of doses affected the results of the trial and will most likely show some positive signals to emerge in the full results that will be presented in April at AAT-AD/PD in Vienna.”
As Brunello noted, DIAN-TU was a preventative trial in subjects with a rare inherited form of early-onset dementia called autosomal-dominant AD and, as these individuals show signs of degeneration at a predictable age, researchers hoped to have clinical efficacy in a small number of the population.
“However, the study was determined not to have achieved its primary endpoint, and Eli Lilly stated that it would not pursue the submission of the drug for approval to treat people with dominantly inherited AD,” Brunello added.
Treating rare diseases
Approximately 90 percent of rare diseases still have no effective treatments, despite regulators implementing expedited approval pathways for these indications. With this in mind, GlobalData pharmaceutical technology writer Allie Nawrat has provided commentary of the areas of clinical trial and data-related challenges, as well as potential game changers in rare disease therapies.
In terms of clinical trial and data-related challenges, Nawrat said that “Regulators and reimbursing agencies still view large, randomized, placebo-controlled trials as the gold standard for measuring safety and efficacy. However, in rare diseases, because of the small patient populations, multiple disease sub-types and diagnosis challenges as clinicians may never have seen this disease before, it is difficult to identify and recruit enough patients with similar disease states into a randomized clinical trial.
“It is also common for regulators to want to see clinically appropriate endpoints that can be compared to placebo groups, but because there have been few previous clinical trials in certain diseases, there is a lack of established endpoints.”
Also, Nawrat noted that placebo groups for rare diseases, particularly those that primarily affect children, are largely viewed as unethical, and there is a call for a patient’s natural history to be used as a comparator.
As far as potential game changers in rare disease therapies, Nawrat pointed out that developing drugs to treat rare diseases is fraught with challenges—these range from trying to recruit from tiny patient populations to fill much-need clinical trials to the complex reimbursement landscape for these innovative, and often bespoke, therapies. As such, Nawrat looked at three case studies of companies on the verge of having treatments for largely ignored rare diseases approved.
First is Rocket Pharmaceuticals’ Fanconi gene therapy, of which Nawrat said, “Fanconi anemia (FA) is a rare paediatric inherited disease caused by a mutation in the FANC genes. Patients with Fanconi experience bone marrow failure as they are unable to create new blood cells. Rocket wants to change this situation with its lentiviral vector gene therapy, RP-L102. It is specifically for Fanconi-A, which is the most common form of the disease.”
RP-L102 is currently in a global registrational Phase 2a study, which has been efficacious and safe in patients so far. Based on these promising signals, RP-L102 has received all accelerated regulatory tools from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA).
Second, there is PTC Therapeutics’ AADC deficiency drug, PTC-AADC, for which the company recently submitted an MAA to the EMA.
“AADC deficiency is a rare condition caused by a mutation in the DDC gene, which leads to issues with the AADC enzyme and subsequent reductions in the production of dopamine. Children suffering with AADC deficiency fail to reach neurological and development milestones and have a high risk of death early in life,” Nawrat said. “PTC’s MAA for its AADC deficiency gene therapy is based on two clinical trials of 26 patients in total.”
Finally, Amryt’s AP101 might become the first drug for epidermolysis bullosa.
As noted by Nawrat: “Epidermolysis bullosa (EB) is a group of rare skin conditions caused by genetic mutations in the genes that encode for the proteins of the skin, particularly in collagen VII. There are currently no approved treatments for this condition, however, UK drug company Amryt is hoping to submit authorization applications to the FDA and EMA by the end of 2021 for its EB drug, AP101.
AP101 is currently being studied in a Phase 3 study, and Amryt says that this is the biggest global EB trial ever undertaken.
Promising pipeline products for dry eye syndrome
Current treatment options for dry eye syndrome (DES) are limited to artificial tears, mostly on its own for milder forms of DES and in combination with anti-inflammatory and corticosteroid therapies for more severe forms of DES. However, this treatment paradigm is expected to see a significant change in the next ten years thanks to a number of promising therapies currently in pipeline development.
According to GlobalData, there are 52 pipeline products in different stages of development, which include Phase 1, 2 and 3 products. Of these 52, 16 are currently in Phase 3 development.
“Current treatment options are limited to corticosteroids and artificial tears, as well as different cyclosporine formulations such as Restasis, Ikervis, Cequa or lymphocyte function-associated antigen-1 (LFA-1) antagonist Xiidra (lifitegrast), all of which principally impart an anti-inflammatory response to alleviate symptoms. In light of these limited options, the number of pipeline products for DES is encouraging,” said Vinie Varkey, senior analyst of neurology and ophthalmology at GlobalData. “Key opinion leaders (KOLs) interviewed by GlobalData were generally excited by the breadth of development in this area, as well as the novel mechanisms of action (MOA) of these pipeline products. Some explore new avenues for tackling DES, such as improving the function of meibomian glands or inhibiting the formation of toxic metabolites, and these have generally boded well with KOLs.”
Latest drug approved for migraine prevention will struggle
Following the news that the FDA had approved Vyepti for the prevention of migraines in adults, Philippa Salter, a neurology and ophthalmology analyst at GlobalData, offered: “Vyepti becomes the latest FDA-approved drug for the prevention of migraines in adults, following the approval of Amgen’s Aimovig, Eli Lilly’s Emgality and Teva’s Ajovy, all of which were approved in the past two years.
“In order to stand out in this crowded market, Lundbeck is drawing attention to the improved dosing schedule of every 12 weeks for Vyepti, which it hopes will give the drug a competitive advantage over the other available drugs, which require dosing every four weeks.”
However, GlobalData expects that Vyepti will not become a first-line therapy for migraine prevention, most likely being used for patients who fail on the other already approved medications. This is reflected in the modest sales GlobalData expects for Vyepti of $566 million in 2025. In comparison, both Aimovig and Emgality are expected to be blockbuster drugs by 2025 with global sales of $1.8 billion and $1.7 billion, respectively.
“Vyepti is administered by intravenous infusion, which is a much more time-consuming and inconvenient route of administration compared with the subcutaneous injection of Vyepti’s competitors,” added Salter.