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Oncology Therapeutics : New Horizons Beyond PD-1/PD-L1 Maturity

Highlights:

  • Since its launch, the immune checkpoint inhibitors market, led by PD-1/PD-L1 inhibitors has reached ~$40 Bn in revenue. The growth is led primarily by Merck’s Keytruda, followed by BMS’ Opdivo, and Roche’s Tecentriq
  • The immune checkpoint inhibitors space is now maturing. The current market spectrum is highly consolidated with top three assets commanding ~90% of the market share
  • To counter the dominance of early movers, new entrants now need to highly strategize their positioning, including combination strategies and targeting of specific patient segments
  • Other innovative approaches in oncology market being pursued includes therapeutic cancer vaccines, CAR-T therapeutics, and CRISPR based gene editing

The PD-1/PD-L1 Journey:

The arrival of PD-1/PD-L1 inhibitors as one of the first immune checkpoint inhibitors in the mix of oncology therapies has been one of the most profound step-ahead in the way oncologists treat cancer worldwide.

The concept of blocking PD-1 and PD-L1 as an effective way of managing cancer was first discussed in the year 2000. Nivolumab (the monoclonal immunoglobulin G4 antibody to PD-1) entered scrutiny of clinical trial by 2006. Industry analysts were very excited once promising clinical data started making rounds in 2012, and finally FDA approved the first immune checkpoint inhibitors in the year 2014.

Since then, multiple approvals across different indications have been sought and the checkpoint inhibitors segment has outpaced the overall growth of oncology market. PD-1/PD-L1 inhibitors market has already reached ~$40 Bn, and is expected to cross the $50 Bn threshold by 2024.

PD-1/PD-L1 Current Market Challenges:

Currently, the immune checkpoint inhibitors have been collectively approved for 15+ indications. The market itself is very concentrated. Keytruda is dominating the market with ~50% market share and FDA approvals in 19 indications and sub-segments. FDA also recognizes Keytruda as the SOC benchmark.

Apart from Keytruda, Opdivo and Tecentriq command a ~30% and ~10% share of the market. Which leaves limited share for other therapies to compete.

For new entrants, regulatory checks are also now more stringent. In March, 2022, FDA had rejected Eli Lilly’s China-developed cancer immunotherapy, sintilimab. Directive was to conduct a SOC comparative trial in the U.S.

In March 2021, FDA Oncologic Drug Advisory Committee had also decided to review the status of therapies granted accelerated approval for specific indications. Following the review, BMS, AstraZeneca, Merck and Roche voluntarily withdrew indications for their cancer drugs.

Opportunities ahead:

To counter the dominance of Keytruda, the newer market entrants need to highly strategize their developmental plans. This includes picking the right combination strategy and targeting of a niche but correct patient segment.

Identifying and focusing on the key differentiators are the most important factors currently for new entrants.

In the immune checkpoint inhibitor story, the biomarkers have always been of value. New players need to incorporate biomarkers into their therapies’ developmental plan. An early partnership with diagnostic players is a necessity for grabbing a foothold among current market dynamics.

New Horizons:

With all the success achieved by immune checkpoint inhibitors market, the key question stands – is there an alternative opportunity that can lead to yet another seismic shift in the way tumors are being treated?

Interestingly, the oncology pipeline is brewing with interesting concepts that may arise in similar market tail-winds as seen with the PD-1/PD-L1 story.

Various forms of targeted oncology therapies are being pursued currently, that includes:

  • Cancer vaccines – A personalized tailor made approach to develop therapeutic vaccines for specific tumor types for each individual
  • CAR-T therapies – Another personalized approach where patient’s immune T-cell is genetically engineered to target the cancer antigens
  • CRISPR/Cas9 based approach – Makes gene editing precise. Application of CRISPR gene editing can be to improve other therapeutic approaches like the CAR-T therapies. Current CAR-T generation can further be improved upon to be more precise with CRISPR enabled precision DNA editing

All these approaches have their own challenges and roadblocks in terms of development and market adoption. However, increasing innovations with each passing day is making the management of cancer better. Longer Overall Survival (OS) rates, Progression Free Survival (PFS) improvements, extended Duration of Response (DoR) and Objective response rates (ORR) are collectively hinting at further expansion of the oncology market and improvement of patient’s lives.

Drug_Pricing_01

U.S. Pharma to Declare War : Fallout from Inflation Reduction Act

Highlights:

  • The Inflation Reduction Act (IRA) of 2022, provides price negotiating power to Medicare for select prescription medications
  • With the bill now turned into law; Medicare can negotiate prices for some of the drugs on which its expenditure is substantial. This may include drugs like Eliquis (Pfizer), Januvia (Merck), Xtandi (Pfizer/Astellas), and Orencia (BMS) among others
  • The U.S. Pharma Industry has geared up to fiercely oppose the act by exploring regulatory, legislative, and legal options

The Backstory:

In May 2019, Novartis had launched a life-saving gene therapy; Zolgensma, for the treatment of pediatric Spinal Muscular Atrophy (SMA). The gene therapy is a game changer in SMA management as its widely considered to be curative. It is given as a one-time IV dose, and replaces the defective SMN 1 gene responsible for the disease.

However, when Zolgensma was launched; the industry was not discussing the therapy’s benefits and life-saving edge. Rather the discussion was concentrated on the price of the therapy – $2.125 million! Zolgensma still retains the title of being the costliest therapy on the planet.

The median annual drug price in U.S. rose to ~$200,000 for the newly launched therapies in 2021. This year so far, this number has surpassed ~$250,000. The price tag of therapies in the US market has always been a topic of hot debate. Often, the topic becomes a focal point of political tussle. Recently however; the legislation passed in the form of the Inflation Reduction Act of 2022 gives Medicare the power to negotiate on select drug prices for the first time in history.

The Act:

Till 2005, Medicare did not cover the outpatient prescription drugs. On January 1st 2006 however, the U.S. congress implemented the Medicare Part D which allowed the payment of outpatient prescription drugs via Medicare. Although the Medicare Part D essentially bars HHS from negotiating prices with the industry.

The Inflation Reduction Act of 2022, now gives the power to HHS to identify drugs on which Medicare spends the maximum and then select them further for price negotiations.

The Threat:

Full effects of the act would only come center-stage after 2026. However, almost all the big-pharma giants are expected to face the ramifications in some way. The Inflation Reduction Act provisions for negotiation of 10 drugs in 2026, 15 in 2027, and 2028. Thereafter 20 drugs each year.

The medications which would be considered for negotiations cannot have a generic or biosimilar alternatives available, and they should be on the approved list for quite some time. The act also aims at limiting the per-patient out of pocket costs at $2,000 per year in Medicare along with forcing the manufacturers to pay rebates for any price hike above the rate of inflation.

Based on Medicare’s 2020 spending, the drugs which can become candidates of price negotiations as per analysts, are Eliquis (BMS), Xarelto (J&J), Januvia (Merck), Imbruvica (Abbvie), Prolia (Amgen), Xtandi (Pfizer/Astellas), and Orencia (BMS) among others.

The act may have its share of impact on the long-term revenue projections, the consequences however do not appear to be significant. The current expectation is that the negotiations would result in reduction of select drug costs by 25%. The act also offers opportunity from the expanded health insurance subsidies that can partially offset the price influences.

The Counter:

PhRMA President and CEO Stephen Ubl called the act a ‘Tragic Loss for Patients’. Industry is gearing up to oppose the act in every shape and form possible. Top executives from J&J, Gilead, AbbVie, Novartis, etc. have all voiced concerns and thoughts on the development in respective earning’s calls.

Among the possible scenarios, the Pharma Industry may sue and enter into litigations to challenge the law as the most likely next step. The attempts can be expected to influence the rulemaking. Other counter strategies being suggested; include offering limited competition to products and limiting the volumes. In essence; the industry is ready to tackle this new law from several fronts.

Blockchain_01

Blockchain : Impact on Bio-Pharma R&D, and Supply-Chain Process

Highlights:

  • A blockchain is a decentralized way of storing and managing data. A decentralized storage provides open, transparent, and secure transaction of data
  • The technology which initiated from digital fund transactions is now impacting every industry that relies on storage and transmission of any kind of digital data. Bio-pharma is certainly no exception
  • Immediate impact of the technology can be felt on clinical trial management and supply-chain supervision. Companies like Novartis, Merck, Boehringer Ingelheim etc. are actively investing in the technology

So, what is it?

In simplified terms, blockchain is a way of storing the data. However, rather than storing the data at one centralized server system, blockchain relies on maintaining identical copies of dataset (shared ledger) on multiple computer systems (nodes) that are controlled and managed by different entities.

These individual; and identical data copies can be called ‘Blocks’ of data, that are interconnected on a peer-to-peer network (‘Chains’). Together forming a Blockchain.

While traditional databases can be edited by a central authority, any alteration to dataset in a blockchain requires consensus agreement from all entities (nodes).

Why is it beneficial?

As blockchain is a decentralized and open format of data storage, all parties involved have a transparent view of information. This in turn provides an auditable trail of data changes that are verifiable, accurate, and secure to all stakeholders.

As the bio-pharma sector relies heavily on information storage and transmission right from the drug discovery to its development through clinical trial process, and finally marketing the therapy by involving mammoth supply-chain networks, the impact of blockchain can be immense.

Privacy of data in blockchain can help in better IP protection, and scientific data publication. Improved data sharing on blockchain can avoid duplication of work resulting in accelerated drug development. Authentic data transmission over a single sharing platform for key stakeholders can hugely assist in clinical trial management.

How it is being implemented?

The primary benefit of the technology appears in management of clinical trials where documentation plays a huge role. Right from the informed consent forms, maintaining identical protocols across trial sites, collecting patient outcomes, etc. the technology can assist in avoiding duplication of work, maintaining authenticity, imparting trustworthiness, and making the overall process seamless.

  • As per an FDA report, almost 10% of trials face issues with informed consent forms. Blockchain can improve this by authentic timestamping, secure storage, and tracking among authorized parties
  • The technology can reduce trial timelines, as clinicians can recruit patients in coordinated manner, and review the outcomes in real time across trial sites
  • Secure, timestamped, and auditable change tracking across the chain, helps in mitigating the risks of lost records, wrong entries, incorrect recruitments, etc. Thereby preventing potential litigations

Apart from clinical trials, the other direct impact is on supply-chain management. As several parties are involved in supply-chain, like manufacturers, local logistics provider, distributers, pharmacies, etc. the transaction of data across these parties runs the risk of incoordination. Inconsistencies between involved parties can also results in product recalls.

One of the initial applications of blockchain in effective supply-chain management is being explored by providing digital medical leaflets to patients.

Who is at the forefront of applying this technology?

Blockchain technology, along with artificial intelligence (AI) and machine learning (ML) is being explored by several big-pharma players to improve their processes.

Boehringer Ingelheim in collaboration with IBM Canada is exploring the application of a decentralized blockchain framework in clinical trials. Novartis, has featured in the Forbes ‘Blockchain 50 2021’ list of top 50 corporations that are leading the efforts of implementing this technology across industries.

FDA had selected Merck, along with IBM, KPMG and Walmart to participate in a blockchain pilot project aimed at developing a tracking and tracing system to adhere with the requirements of the Drug Supply Chain Security Act (DSCSA).

AbbVie, AstraZeneca, Pfizer, Roche, GSK, Bayer, Janssen, and UCB are few of the key big-pharma players involved in an EU blockchain consortium – PharmaLedger that’s currently focused upon building scan codes for package inserts, eConsent for remote clinical trials, and improved collection of health data. In essence, while Blockchain technology’s implementation in bio-pharma is only at a nascent stage currently, there is little doubt on its widespread adoption across the pharma drug value chain in immediate future, resulting in shrinkage of both – drug development costs, and timelines.